[Chronic myeloid leukemia (CML): a therapeutic dilemma].
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Biomedical subjects
E Carreras
Publications and source records attributed to E Carreras.
[Allogenic bone marrow transplantation in multiple myeloma. Analysis of 12 consecutive cases].
BACKGROUND: Allogeneic bone marrow transplantation (BMT) is the only potentially curative treatment in multiple myeloma (MM). METHODS: From january 1986 to december 1993, 12 cases (10 males and 2 females) underwent BMT in the authors' institution. The mean age of the series was 39 years (range 23-49). The situation of the myeloma on initiation of the conditioning was: complete remission (CR) in 2 cases, objective response in 5 cases, partial response in 1 case and treatment resistance in 4 cases. The conditioning schedule included cyclophosphamide (120 mg/kg) and total body irradiation (10-14 Gy) with or without melfalan at high doses in 11 patients and busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in 1 case. The prophylaxis of graft versus host disease (GVHD) was carried out with methotrexate and cyclosporine A (CsA) in 7 cases, CsA plus prednisone in 2 cases and 3 patients received CsA plus bone marrow partially depleted of T lymphocytes by elutriation. RESULTS: The situation of the myeloma with regard to response following transplantation was: unevaluable in 1 case, resistant in 1 case, objective response in 2 cases and CR in 8 cases. Seven out of the 10 patients at risk presented grades II-IV GVHD. Four of the 8 patients who were in CR following transplantation died due to post transplant complications and 2 out of the 6 relapsed 9 months after the transplant while 2 remain in CR at 5 and 8 years after the transplant, respectively. Nine patients died due to infection in 2 cases, GVHD and infection in 4 cases, GVHD and hemorrhage in 1 case and progression and infection in 2 cases. Of the 3 surviving patients, 1 relapsed at 14 months after the transplant and two remain in CR at 5 and 8 years post transplantation. CONCLUSIONS: Bone marrow transplantation conditioning gives place to a high number of complete remission in multiple myeloma. However, the incidence of acute grade II-IV graft versus host disease and mortality due to complications related to the transplantation are very high. Nonetheless, a proportion of patients may achieve curation with bone marrow transplantation.
Adult↗
[Bone marrow transplantation from unrelated donors in chronic myeloid leukemia: the results in 15 patients].
BACKGROUND: Bone marrow transplantation (BMT) from a histocompatible donor is the only curative treatment in chronic myeloid leukemia (CML). Only a minority of patients dispose of an adequate donor from among his/her relatives. The remaining transplant receptors must look to unrelated donors (URD). The experience of the Escuela de Hematología Farreras Valentí (Farreras Valentí School of Hematology, Barcelona, Spain) in BMT from URD in CML in the first chronic phase is herein reported. METHODS: Fifteen patients (9 males and 6 females, median age 33 years; range 14-48 years) were transplanted from October 1988 to May 1994. Serologic identity was expressed in the A, B and D loci in 9 cases and minor incompatibility in 6. Conditioning included total body irradiation and cyclophosphamide in 14 patients and busulphan plus cyclophosphamide in 1. Partial and selective T lymphocyte depletion was performed by elutriation in 7 cases. RESULTS: Primary implant failure was detected in 2 out of 14 risk patients (14%) and secondary failure was observed in 3 out of 12 cases (25%). The actuarial probability of acute graft versus host disease (GVHD) was 55 +/- 15% at 7 weeks with a probability of appearance with an intensity of II-IV of 31 +/- 13%. Five out of 7 patients with a survival of greater than 100 days, developed chronic GVHD (71%). Ten presented fatal complications. In 5 cases, death was due to pulmonary problems. Recurrence of CML was not observed in any of the patients in the series. The probability of disease free survival at 2 years was 30 +/- 12%. CONCLUSIONS: Bone marrow transplantation from an unrelated donor is an effective treatment for a proportion of patients with chronic myeloid leukemia although severe complications are frequent and originate a high mortality.
Adolescent↗
Interleukin-2 after T-cell-depleted allogeneic bone marrow transplantation.
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Adult↗
Assessment of histopathologic changes in the colonic biopsy in acute graft-versus-host disease.
The authors reviewed 78 colonic biopsies from 63 patients undergoing bone marrow transplantation (BMT), 56 allogeneic and 7 autologous, to assess different morphologic changes related with intestinal acute graft-versus-host disease (A-GVHD). Only five biopsies were done before the 20th day after BMT. The authors studied the presence of ulcers and atrophy in the mucosa, the nuclear atypia, and inflammatory infiltrate in the surface epithelium, and the architectural abnormalities, as well as dilation of the glands, and the presence of crypt abscesses. The authors explored the glandular epithelium for apoptosis and intraepithelial lymphocytes. They examined the lamina propria for inflammatory infiltrate, especially for so-called "focal periglandular infiltrate (FPGI)," edema fibrosis, increase of capillary vessels and presence of muciphages and clusters of enterochromaffin cells. Cases were grouped according to clinical symptoms and histologic diagnosis of A-GVHD in skin or liver. Group A had 15 asymptomatic cases (control). Group B had 20 cases from asymptomatic patients with a histologically proven A-GVHD. Group C had 43 cases with gastrointestinal symptoms and histologically proven A-GVHD. Then, the relative frequency of every histologic feature previously described were compared in the different groups by means of an univariate analysis. Apoptosis of the glandular epithelium was found in 48 cases, two of them in patients carrying an auto-BMT. Focal periglandular infiltrate was found in 11 cases that was associated with apoptosis (P < .03, Fisher's exact test). In this series, the presence of FPGI was linked with finding apoptosis in a given specimen with a probability of 91%. Glandular architectural changes and dilation were also more frequent in group C than in groups A and B when compared in the univariate analysis.
Acute Disease↗
Diffuse alveolar hemorrhage in allogeneic bone marrow transplantation. A postmortem study.
To define better the syndrome of diffuse alveolar hemorrhage (DAH), we conducted a postmortem study in 77 patients who died of pulmonary complications, distributed into three groups. Group A included 47 patients with hematologic diseases treated with allogeneic bone marrow transplant (BMT); Group B, 20 patients with hematologic diseases treated with conventional chemotherapy; and Group C, 10 patients without hematologic diseases. The diagnosis of DAH was established when there was blood in at least 30% of the lung tissue evaluated without evidence of infection or any other pathologic change that could account for its presence. The presence of an associated pulmonary complication was considered only when there was normal lung parenchyma between both blood and the specific lesions. Diffuse alveolar hemorrhage was shown in 11 patients in Group A (23%) compared with 1 patient in Group B (5%) (p < 0.05). Of the 11 patients with DAH in Group A, 10 had some associated pulmonary complication: 7 presented with diffuse alveolar damage (DAD), 2 with associated bacterial pneumonia and 1 with invasive aspergillosis, 2 others had an associated cytomegalovirus (CMV) pneumonitis, and the remaining patients had an associated herpes pneumonia. There were no clinical differences between patients with and without DAH. Of 8 patients with confirmed DAH in Group A, who had been submitted to a bronchoscopic examination within 1 wk of death, 4 had normal BAL fluid; by contrast, 7 of 13 patients without DAH had hemorrhagic BAL fluid.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Role of cyclosporine metabolites and clinical toxicity in organ transplantation.
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Adult↗
Anti-D antibody of exclusive IgM class after minor Rh(D)-mismatched BMT.
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Adolescent↗
[Intravenous amphotericin B as prevention of deep mycoses in allogeneic bone marrow transplantation].
BACKGROUND: To evaluate the efficacy of i.v. amphotericin B (AmB) as prophylaxis of deep mycosis (DM) in allogenic bone marrow transplantation (BMT). METHODS: From July 1991 to May 1993, 45 consecutive patients treated by allogenic BMT with no previous history of systemic mycosis and with normal renal function were administered prophylactic AmB at a dose of 0.5 mg/kg/48 h from day + 1 BMT until hemoperipheral recovery (group A). These were compared with an historic control group made up of 45 consecutive patients submitted to BMT from January 1990 to June 1991 who did not receive prophylactic AmB (group B). During the neutropenic phase all the patients remained in isolation units with laminar flow of filtered air and were administered oral non absorbable antibiotic therapy and diet of low bacterial content. The incidence of DM and the dose of AmB administered during the first 120 days post BMT were evaluated. RESULTS: In the first 30 days following BMT 3 (7%) cases of DM were observed in group A and 3 (7%) in group B. Four (9%) additional cases were found from days 30 to 120 in group A and 3 (7%) in group B. In 3 (7%) patients of the group which received prophylaxis and in 4 (9%) of the control group Candida spp. was isolated. In 3 (7%) patients from group A and 1 (2%) patient from group B the infection was due to Aspergillus. Although the patients from group A received therapeutic AmB less frequently (78% vs 91%) and later (13 [SD +/- 5.9] vs 9.2 [SD +/- 4.6] days) than those of group B (p < 0.002) the mean dose of AmB per patient treated was similar in both groups (11.3 [SD +/- 8.8] vs 11.8 [SD +/- 7] mg/kg). CONCLUSIONS: The prophylactic use of systemic amphotericin during the neutropenic phase of bone marrow transplantation does not reduce either the incidence of deep mycosis or the mean dose of amphotericin administered.
Adolescent↗
[The prognostic factors of early mortality in bone marrow transplantation in patients with chronic myeloid leukemia].
INTRODUCTION: The use of bone marrow transplantation (BMT) in leukemia treatment is associated with high early morbid-mortality rates. Therefore, to identify morbid-mortality risk factors in this setting can be useful to improve therapeutic ratio. METHODS: We studied 15 variables in 46 patients with chronic myeloid leukemia (CML) treated with cyclophosphamide, total body irradiation (TBI) and allogeneic BMT. A multivariant analysis with an unconditional logistic regression model was used. RESULTS: Variables found to be related with early mortality included general state of health and acute graft versus host disease. Patients with a Karnofsky index (KI) between 60% and 80% had a higher risk of early death than those with a KI between 90 and 100%. Patients who developed severe (grade II-IV) acute graft versus host disease (AGVHD), had a relative risk of 15.62 (IC 95%: 3.16-77.34) compared with those who do not. Time between diagnosis and BMT contributed to the creation of the mathematical model without reaching statistical significance. CONCLUSIONS: In this series and in the range of the parameters analysed, general state of health according to KI, and the appearance of severe AGVHD are the variables related with a higher risk of early mortality.
Acute Disease↗
Different response to recombinant human granulocyte-macrophage colony-stimulating factor in primary and secondary graft failure after bone marrow transplantation.
The efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in graft failure after bone marrow transplantation (BMT) has been evaluated in 25 patients. rhGM-CSF was administered intravenously at a dose of 5 or 10 micrograms/kg. Fourteen patients (seven allogeneic BMT [allo-BMT], seven autologous BMT [ABMT]) were treated for primary bone marrow failure (no granulocyte recovery after BMT), and 11 cases (all allo-BMT) received rhGM-CSF for secondary bone marrow failure (absolute neutrophil count lower than 0.5 x 10(9)/L after a previously sustained granulocyte recovery). Two allo-BMT and three ABMT patients with primary bone marrow failure achieved a granulocyte response to rhGM-CSF. In contrast, nine patients with primary graft failure did not respond to rhGM-CSF (four ABMT, three HLA-identical T-depleted BMT, one minor mismatch BMT, one unrelated BMT). Ten of 11 allo-BMT patients treated for secondary bone marrow failure attained an ANC higher than 0.5 x 10(9)/L, but most became severely neutropenic again at a median time of 4 weeks. The possible cause triggering graft failure (graft-vs.-host disease [GVHD], cytomegalovirus [CMV] infection) remained unsolved in most of these cases. Actuarial probability of survival of the entire series was 16 +/- 9% at 15 months. The severity of graft failure and the presence of other concomitant complications in most of our patients may justify these poor results. In conclusion, rhGM-CSF had less efficacy in patients with primary bone marrow failure than in those with secondary bone marrow failure. In the latter setting, measures addressed to correct the initial cause of graft failure are mandatory.
Adolescent↗
On the reliability of clinical criteria for the diagnosis of hepatic veno-occlusive disease.
Among 217 patients who received an allogeneic (136 cases) or autologous (81 cases) bone marrow transplant, the diagnosis of hepatic veno-occlusive disease (VOD) was established in 38 according to Seattle clinical criteria. Thirty-two underwent a transjugular liver biopsy and measurement of the hepatic venous pressure gradient (HVPG). The study was completed in 30 patients with no serious complications. Hepatic VOD was histologically confirmed in 18 patients (60%); the remaining 12 were classified as non-VOD. An increased HVPG discriminated well between VOD and non-VOD cases. Thus, hemodynamic data can considerably reinforce the accuracy of histological diagnosis. The predictive value of two vs. three clinical data of the Seattle criteria was analyzed. Among the 19 cases fulfilling two clinical data VOD was confirmed in only eight (42%), whereas VOD was proved in ten of 11 cases (91%) (p = 0.02) suspected on the basis of three clinical data. When reliability of the Baltimore clinical criteria was analyzed, the result was identical to that observed when three Seattle clinical data were present. The specificity of the latter classification was high (92%) while its sensitivity was relatively low (56%). In conclusion, clinical criteria are not reliable for either recognizing or excluding the diagnosis of VOD. Thus, a transjugular liver biopsy, associated with hemodynamic evaluation, is strongly recommended when VOD is clinically suspected.
Adolescent↗
Hepatic veno-occlusive disease after bone marrow transplant.
Hepatic veno-occlusive disease (VOD) is a non-thrombotic obliteration of the lumina of small intrahepatic veins. VOD has been reported after exposure to a wide variety of pathogens. It has been suggested that the chemoradiotherapy used as the conditioning regimen for bone marrow transplant (BMT) is now the main cause of this disease. However, the pathogenesis of VOD after BMT is probably multifactorial. Endothelial injury of sinusoids and small hepatic veins is considered to be the initial event in genesis of VOD. This injury is followed by deposition of fibrin-related aggregates in the subendothelial zone. These aggregates, and the intramural entrapment of fluid and cellular debris, occlude progressively the hepatic venous outflow and generate a postsinusoidal intrahepatic hypertension. Clinically, VOD is characterized by jaundice, weight gain, ascites, painful hepatomegaly and platelet refractoriness developing early post transplant, although other posttransplant liver disturbances can produce a similar syndrome. VOD diagnosis is usually established by applying the clinical criteria proposed by the Seattle and Baltimore groups. When clinical diagnosis of VOD is uncertain, a transjugular liver study including a transvenous biopsy and measurement of the gradient between wedged and free hepatic venous pressure, is recommended in order to establish an accurate diagnosis. According to the literature data, the incidence of VOD ranges from 0 to 70% and its mortality from 20 to 50%. This very wide range is attributable to the different incidence of risk factors in the different series and to the differences in applying the diagnostic criteria.(ABSTRACT TRUNCATED AT 250 WORDS)
Antineoplastic Agents↗
Risk factors for early mortality in allogeneic bone marrow transplantation. A multivariate analysis on 174 leukaemia patients.
Allogeneic bone marrow transplantation in patients with leukaemia is an aggressive therapeutic procedure which implies high early mortality. Current opinion trends attribute the greater part of the procedure toxicity to the preparative regimen. The results of a multivariate analysis on data of 174 leukaemia patients conditioned with total body irradiation (TBI), 10-12 Gy, single dose or fractionated, and lung shielding at 8 Gy, plus chemotherapy: cyclophosphamide 120 mg/kg, before or after TBI, are presented. The variables statistically related with early mortality are age, Karnofsky index (KI) and acute graft-versus-host disease (GvHD). No variable depending on radiotherapy reached the significance level. The relative risk of early mortality for patients older than 26 years, in bad general condition (KI < 90%), or developing acute severe (grades II-IV)GvHD, is 3.99, 5.68, and 6.71, respectively. We conclude that in the range of TBI schedules analysed, radiation therapy is not an important factor in early death, but acute severe GvHD, or recipient's bad general condition are factors to be improved by bone marrow transplantation teams if they want to improve the therapeutic index of the procedure.
Adolescent↗
Sonographic diagnosis and hemodynamic correlation in veno-occlusive disease of the liver.
This study evaluated the role of duplex Doppler sonography in the diagnosis of VOD of the liver after bone marrow transplantation. Sixteen patients with clinical criteria of VOD were studied. The final diagnosis was achieved by transjugular liver biopsy, and the hepatic venous pressure gradient was measured during the procedure to estimate portal pressure. Nine patients (56.2%) had histologically proved VOD. Gallbladder wall thickening was present in 75% of patients with VOD, but in none of those without it (P = 0.01). Gallbladder wall thickening and ascites were present only in patients with portal hypertension. Nine patients (five with VOD and four without it) also were evaluated with duplex Doppler sonography, and no obvious flow abnormalities were detected in the portal vein and hepatic veins. These results suggest that sonography is useful in detecting early signs of portal hypertension pointing to the diagnosis of VOD in patients with bone marrow transplantation.
Adolescent↗
[Immunophenotyping study of bone marrow fractions obtained by elutriation in allogeneic bone marrow transplantation].
PURPOSE: Bone marrow transplantation (BMT) is an effective treatment for acute and chronic leukaemias. Lymphocyte depletion of donor bone marrow for preventing GVHD has been associated with a higher incidence of relapse after allogeneic BMT. This association suggests an antileukaemic effect of donor lymphocytes. In vitro studies show that cytotoxic T lymphocytes (CD3+ CD56+) and NK cells (CD3-CD56+) have an antileukaemic effect. To know which specific subpopulation of lymphocytes are depleted by counterflow centrifugation or elutriation, we analysed B, T, NK cells and hematopoietic precursors in the marrow fractions after this procedure. PATIENTS AND METHODS: Eight patients (6 CML, 1 ALL, 1 B-CLL) received an allogeneic BMT with lymphocyte depletion of the bone marrow graft using elutriation. After a Percoll gradient, donor marrow mononuclear cells (MNC) were separated with this method in five fractions (F1 to F5). RESULTS: Lymphocyte depletion of donor marrow was in average of 1.7 log. This depletion was also selective, the last fraction containing higher number of cytotoxic T lymphocytes and NK cells than the other fractions. Recovery of CD34+ cells in the four fractions concerning to post-Percoll marrow was 84%, most of them being in the last fraction. CONCLUSIONS: The use of elutriation for lymphocyte depletion is a good method for graft manipulation with the feasibility to adjust a lymphocyte/Kg. dose. Elutriation may be effective in reducing the incidence and severity of graft versus host disease and preserving the antileukaemic effect.
Adult↗
Bone marrow transplantation for chronic myeloid leukemia: long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation.
The data on 1480 bone marrow transplants for chronic myeloid leukemia (CML), performed between 1979 and 1990 were reported to the registry of the European Group for Bone Marrow Transplantation (EBMT). Of these, 1082 patients were transplanted in first chronic phase, 88 in subsequent chronic phase, 251 in accelerated phase and 59 during blast crisis. For these four disease stages leukemia-free survival (LFS) at 5 years is 39%, 22%, 22% and 0%, respectively. A more detailed analysis was performed for 947 patients receiving a first transplant in first chronic phase of their disease from an HLA-identical sibling donor. Survival at 8 years is 47%. At 5 years, relapse incidence (RI) is 33% and the transplant-related mortality rate (TRM) is 42%. The major prognostic factors are patient age (LFS, TRM), T cell depletion (LFS, RI), time from diagnosis to transplant (LFS, TRM), white blood cell count (RI) and donor-recipient sex combination (LFS, TRM). This first report on long-term results of a large cohort of transplanted CML patients confirms and extends previous findings. Stage of disease at time of transplant is the most important prognostic factor. Fifty per cent of all patients transplanted for CML in chronic phase can be expected to be alive at 8 years post-transplant, 40% alive and free of the disease. This number increases to > 60% for patients given cyclosporin and methotrexate without T cell depletion as GVHD prophylaxis. However, there is no plateau phase and late relapses and late transplant-related deaths occur in all subcategories.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Autologous bone marrow transplantation for acute leukemia: results and prognostic factors in 90 consecutive patients.
The results of autologous bone marrow transplantation (ABMT) in acute leukemia (AL) and the prognostic factors for outcome were analyzed in a series of 90 consecutive patients treated at a single institution (mean +/- SD age: 25 +/- 11 years). Diagnosis was: AML (n = 43), ALL (n = 44), acute undifferentiated leukemia (n = 2) and acute bilineage (n = 1). Disease stage at ABMT was: first complete remission (CR1) 46 cases, CR2 33, other stages 11. Conditioning consisted of cyclophosphamide and total body irradiation in 88 patients. The 3 year probability of disease-free survival (DFS) was influenced by disease stage at ABMT: CR1 48%, CR2 28%, CR3 plus CR4 15%. The characteristics associated with a high probability of relapse were: in AML a FAB subtype other than M1 or M3 (p = 0.01) and in ALL an interval between CR1 and ABMT of < 3 months (p = 0.002). A WBC > 15 x 10(9)/l at diagnosis (p = 0.01), splenomegaly at diagnosis (p = 0.002) and time to CR1 > 4 weeks (p = 0.06) increased the risk of relapse in the entire group in CR1. In multivariate analysis, WBC at diagnosis (p = 0.006) and disease stage at ABMT (p = 0.03) independently influenced DFS. This study confirms the encouraging results of ABMT in CR1 but further antileukemia measures are necessary in patients with adverse prognostic features.
Acute Disease↗