Biomedical subjects
Publications and source records attributed to F Frassoni.
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Twenty-five patients with hematologic malignancies (n = 21) or aplastic anemia (n = 4) undergoing an allogeneic BMT from an HLA-identical sibling developed cytomegalovirus (CMV) antigenemia at a mean interval from BMT of 41 days (range 16-141 days). All patients were treated at the time of antigenemia in the absence of other signs of CMV disease with ganciclovir (n = 13) or foscarnet (n = 12) if the WBC count was < 2.5 x 10(9)/l or the patient had aplastic anemia. The two groups were comparable for age, sex and disease status. There were more patients receiving T cell-depleted grafts in the foscarnet group (58% vs 15%, p = 0.003). The first course of treatment was planned to last a minimum of 10 days: foscarnet was given at 180 mg/kg/day, and ganciclovir at 10 mg/kg/day. Patients still showing pp65-positive cells continued treatment in the absence of adverse effects such as cytopenia and/or increased creatinine levels. Maintenance treatment was given for 3-4 weeks. End-points of the study were (1) clearing of CMV antigenemia, (2) tolerance and side-effects, and (3) progression to CMV disease. Both agents were effective in clearing CMV antigenemia: 14 of 25 patients were CMV antigen-negative by day 14 of treatment and all surviving patients were negative by day +50. Renal toxicity was seen mainly in the foscarnet group but caused discontinuation of the drug only in one patient. Myelotoxicity was seen in the ganciclovir group and again could be controlled in 12 of 13 patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Eleven patients underwent bone marrow transplant (BMT) from an HLA-identical sibling following single dose total body irradiation (TBI), with in vivo and ex vivo T cell depletion (TCD). In spite of CMV prophylaxis with acyclovir and high-dose i.v. Ig, 10 of 11 patients developed CMV antigenemia, at a median interval from BMT of 34 days (range 16-72 days) and five died with CMV disease. Foscarnet was then given prophylactically in 11 additional TCD patients to test whether we could (1) prevent CMV reactivation, and (2) reduce transplant-related mortality. Foscarnet was given daily from days +10 to +15 (180 mg/kg/day), then thrice weekly (90 mg/kg/day) until day +100. Five patients developed CMV antigenemia at a median interval from BMT of 42 days (range 16-65 days); one progressed to CMV pneumonitis and died. The risk of developing CMV antigenemia within day 100 is currently 91% for the historical control group and 45% for the foscarnet group (p = 0.005). At diagnosis of CMV, the median number of CMV antigen-positive cells was 6.5 (range 1-13) vs 1 (range 1-5) in acyclovir vs foscarnet patients (p = 0.02) and the median highest number of CMV antigen-positive cells was 7 (range 3-110) vs 1 (range 1-12), respectively, (p = 0.03). The actuarial 1 year transplant-related mortality (TRM) is 49% and 13% in the two groups (p = 0.08). This study suggests that foscarnet prophylaxis starting on day +10 post-BMT may be helpful in reducing the risk of CMV disease and early mortality following TCD BMT.
Acute promyelocytic leukemia (M3) is a distinct subtype of AML considered to have better response to chemotherapy and a higher cure rate than other subtypes. We analyzed the outcome for 362 M3 patients transplanted in Europe from November 1979 to December 1992 and reported to the acute leukemia registry of the European Cooperative Group for Bone Marrow Transplantation (EMBT). Of these 362 patients, 187 received an autograft, 129 in first remission (CR1) and 58 in second remission (CR2), and 175 an allograft, 142 in CR1 and 33 in CR2. Patients autografted in CR1 had at 7 years a leukemia-free survival (LFS) of 48 +/- 5%, a relapse rate (RR) of 41 +/- 5% and a probability of transplant-related mortality (TRM) of 18 +/- 6%. Patients allografted in CR1 had a LFS of 42 +/- 6%, a RR of 28 +/- 5% and a TRM probability of 42 +/- 8%. For patients transplanted in CR2, the respective figures after auto and allotransplantation were: LFS: 31 +/- 7% and 22 +/- 8%, RR: 54 +/- 8% and 64 +/- 11%, TRM: 23 +/- 9% and 40 +/- 9%. These data, which do not permit comparison between autologous and allogeneic BMT, indicate that roughly 45% of M3 patients achieving CR1 may be cured by a marrow transplant. Since the recent use of transretinoic acid-containing induction regimens has increased early control for patients with AML M3, it will be important to find out how these results affect outcome following allogeneic or autologous BMT.
Ninety-one patients with de novo acute myeloid leukemia (AML) in first complete remission (CR) undergoing an HLA-identical sibling BMT and with a minimum follow-up of 12 months were analyzed for disease-related and transplant-related variables predicting survival and relapse. The overall actuarial 5 year survival is 53% and the relapse rate 29%, with a medium follow-up for surviving patients of 1552 days (range 365-4094 days). In univariate analysis the following variables were found to be associated with an increased risk of failure: high-dose cyclosporin (CsA), M4-M6 FAB subtype and a long interval (> or = 180 days) between diagnosis and BMT. Other disease-related variables at presentation were not significant, including WBC count > 50 x 10(9)/l, marrow blasts < 70%, time to enter remission > 40 days and > 2 courses to enter remission. Survival was 58% vs 43% for M1-M3 vs M4-M6 FAB subtypes (p = 0.03) and 71% vs 42% for low-dose vs high-dose CsA (p = 0.01). A multivariate analysis was then run separately on survival, relapse and transplant related mortality (TRM). Survival was negatively influenced by M4-M6 FAB subtypes (p = 0.009), high-dose CsA (p = 0.03) and a long interval between diagnosis and BMT (p = 0.04). Leukemia relapse was higher in patients receiving high-dose CsA (p = 0.003) and in females (p = 0.04). Transplant-related mortality was higher in FAB M4-M6 patients (p = 0.01) and patients grafted late after diagnosis (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
We investigated the occurrence of late events (beyond 2 years) in patients with acute leukaemia who received an allogeneic (BMT) (n = 1059), or an autologous bone marrow transplantation (ABMT) (n = 656) in Europe during the period from January 1979 to December 1990. Patients with no recurrence of leukaemia at 2 years had overall 82% chance of being alive in complete remission at 9 years following transplantation regardless of the nature of the leukaemia, the status at transplant, and the type of transplant. The incidence of late relapses continuously decreased with time. The latest relapses in acute myelogenous leukaemia (AML) were observed following BMT at 6.6 years in a patient transplanted in first remission (CR1) and at 3.7 years in a patient transplanted in second remission (CR2), and following ABMT at 6 years and 5.1 years respectively. The latest relapses in acute lymphoblastic leukaemia (ALL) were observed following BMT at 4 years in a patient transplanted in first remission (CR1) and at 6.8 years in a patient transplanted in second remission (CR2), and following ABMT at 5.3 years and 4.5 years respectively. Several factors predictive for late relapse or death were identified. Patients allografted experienced a lower frequency of late relapse than patients autografted. Of the numerous other prognostic factors studied, female sex in AML, the use of total body irradiation (TBI) in ALL and status in CR1, rather than CR2-3, for both ALL and AML allografted were correlated with a lower relapse incidence. The use of TBI in ALL was also associated with a better LFS and survival. The absence of acute graft-versus-host disease (GVHD) in allografted AML correlated with better LFS and better survival, but had no influence on the relapse incidence. This study indicates that patients alive and well at 2 years post transplant have a very high probability of being cured, but the possibility of late relapse still remains.
We studied the clinical course of 130 chronic myeloid leukemia (CML) patients (89 males and 41 females) in the European Bone Marrow Transplantation Group (EBMT) registry who received transplants before January 1, 1988 and who subsequently had evidence of recurrent leukemia. All patients had received a pretransplant conditioning regimen including total body irradiation (TBI). The first evidence of relapse was cytogenetic only in 74 (57%) patients and hematologic in 56 (43%). The overall actuarial survival from relapse was 36% at 6 years, with a significantly higher proportion of survivors among female patients (53% v 30%; P < .002). In univariate analysis, the 6-year probability of survival was 52% for patients with cytogenetic relapse and 30% for patients relapsing in chronic phase (CP), while no patient who relapsed in advanced phase (AP or BC) survived more than 3.5 years from relapse (P < .0001). The actuarial survival of patients relapsing before 6 months, between 6 and 12 months, and later than 12 months after transplant was 27%, 26%, and 45%, respectively (P < .002). Among patients with cytogenetic relapse, partial or complete disappearance of Ph-positive cells occurred in 40% of untreated patients and in 42% of those treated with interferon (IFN). However, IFN therapy significantly delayed progression toward hematologic disease. Cytogenetic responses were observed in 25% of patients who received IFN for relapse into CP, while only one minor cytogenetic response was reported in patients on conventional chemotherapy. For patients presenting with cytogenetic relapse as well as for those in hematologic relapse, IFN therapy significantly improved the 2-year probability of survival. However, long-term survival for IFN-treated patients in either group was not different from long-term survival in comparable patients not receiving IFN therapy. Twenty-nine patients of this series underwent a second bone marrow transplant (BMT) and the projected survival at 4 years after the second transplant is 28%. In multivariate Cox regression analysis, four factors remained significantly associated with survival: disease phase at relapse (P < .0001), duration of time interval from BMT to relapse (P = .0001), interferon therapy at relapse (P = .0024), and patient sex (P = .0032). This retrospective study provides evidence that some patients who relapse after BMT may benefit from treatment with IFN; a second BMT may offer the chance of cure. Data from this analysis may be useful in designing future prospective trials on posttransplant CML relapse.
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Twenty-seven patients with chronic myelogenous leukemia (CML)--17 in the chronic phase and 10 in the accelerated phase--were treated with an intensive chemotherapy regimen consisting of idarubicin, arabinosylcytosine, and etoposide. All patients were ineligible for bone marrow transplantation (BMT) and showed little or no cytogenetic response to interferon alpha (IFN-alpha). Blood hemopoietic cells (BHC) were collected by leukapheresis in all patients during early recovery from chemotherapy-induced aplasia. In 13/27 patients (48%), all metaphases were Ph-negative (Ph-); in another five patients, the percentage of Ph-positive (Ph+) metaphases decreased to less than 50%. Complete Ph+ disappearance was found in 66% of the patients treated within two years of diagnosis and in only 30% of those treated later. The collected Ph- cells have been used as autotransplants in nine patients: seven have shown sustained engraftment, and five are alive and well, with Ph- at 3+, 4+, 7+, 11+, and 19+ months after transplant. It is remarkable that one patient, now Ph- at 19 months after transplant, is also PCR negative. These results suggest that it is possible to collect Ph- hemopoietic cells even years after diagnosis and to perform autologous transplants with these cells.
Two hundred and twenty-nine patients with chronic myeloid leukaemia in chronic phase awaiting bone marrow transplantation from an HLA-identical sibling donor were randomized as part of their conditioning, to receive splenic irradiation (SI+, 115 patients), or not (SI-, 114 patients). Both groups were identical in regard to age, sex, donor/recipient sex combination and disease activity. Survival, leukaemia-free survival, incidence of transplant-related mortality, acute and chronic graft versus host disease, incidence of rejection and probability of relapse were not different in either groups at a median follow-up time of 4.5 years (minimum follow-up 2 years). Recovery of peripheral white blood cell counts to 1 x 10(9)/l but not of platelet counts to 50 x 10(9)/l was significantly faster in patients with SI+ (21 vs 24 days). This small benefit does not justify routine splenic irradiation prior to BMT, in CML.
Twenty-five patients with CML (chronic phase (CP): 15 patients; accelerated phase (AP): 10 patients) at a median of 40 months after diagnosis and ineligible for allogeneic BMT, received an intensive chemotherapy regimen consisting of idarubicin, intermediate-dose ara-C and etoposide (ICE protocol). All patients had previously received alpha-interferon and only two patients had had partial cytogenetic response. During recovery from chemotherapy-induced aplasia, blood progenitors cells (BPC) were harvested by leukapheresis. All metaphases were found to be Ph-negative in the collection of 12 of 25 (48%) patients (CP: 9 of 15 (60%), AP: 3 of 10 (30%)) and a decrease of < 50% Ph-positive metaphases was seen in an additional five (CP: 4 patients; AP: 1 patient). The percentage of complete Ph-disappearance was 66% in patients receiving this procedure within the first 2 years of diagnosis and 30% in those treated after the second year of diagnosis. So far, the Ph-negative collections have been used in 9 patients (CP: 8 patients; AP: 1 patient) as autograft after conditioning with total body irradiation/etoposide/CY. Seven of 9 patients engrafted and 5 are alive and well, Ph-negative at 2+, 3+, 6+, 10+ and 18+ months.
Patients with chronic granulocytic leukemia (CGL) can be classified in different groups according to risk factors at diagnosis (Sokal). The aim of the present study was to assess the impact of Sokal's risk factors in 100 patients with CGL undergoing allogeneic BMT. Patients were in first chronic phase (CP) (n = 65), or with advanced disease (n = 35), grafted from an HLA-identical sibling following conditioning with cyclophosphamide and total body irradiation (TBI). Median follow up for survivors is 1783 days (429-3533 days). Variables recorded at diagnosis to calculate Sokal's prognostic index were: leukocyte, platelet and peripheral blood blast cell counts, age and spleen volume. The median value of the Sokal index was 0.87. Projected survival for all patients at 9 years was 28% (95% confidence limits (CL) 6-49), 48% (34-62) for first CP patients and 15% (0-36) for more than first CP patients (p = 0.04). Survival was 25% and 31% for all patients with a Sokal index of < 0.87/> or = (p = 0.07) and 55% vs 39% for first CP patients only (p = 0.03). The relapse rate was similar for patients with Sokal index < 0.87/> or = (41% vs 39%, p = 0.9) and this was also true for first CP patients (33% vs 26%, p = 0.8). In multivariate analysis, an interval between diagnosis and BMT of > 2 years was the most significant negative predictor for survival for the whole group of patients (p = 0.01) and more so for first CP patients (p = 0.0004).(ABSTRACT TRUNCATED AT 250 WORDS)
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)
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In the attempt to evaluate the role of Autologous and Allogeneic Bone Marrow Transplantation, we have retrospectively analyzed 159 patients with Acute Myeloid Leukemia in first complete remission treated in our Unit, most of whom were referred from other Institutions. High-dose therapy was uniform and consisted of cyclophosphamide 60 mg/kg/d on two consecutive days and TBI in a single dose (10 Gy) for ABMT patients and in fractionated doses (3.3 Gy x 3 days) for BMT patients. Eight years actuarial survival was similar in two groups (52% for BMT and 49% for ABMT). The actuarial risk of relapse for BMT and ABMT was 29% and 43%, respectively. Considering that none of ABMT patients was "purged" with in vitro technique, this review seems to confirm the importance of "in vivo" purging with postremission intensification, immediately before the harvesting. Of course, more patients and a longer follow-up are needed to draw final conclusions.
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A total of 239 patients with chronic myeloid leukaemia (CML) in chronic phase awaiting bone marrow transplantation (BMT) from an HLA-identical sibling donor were randomized to receive, as part of their conditioning, splenic irradiation (SI+) or no splenic irradiation (SI-). There was no difference between the SI+ and SI- groups regarding the distribution of age, sex, donor/recipient sex combination and blood counts at diagnosis and at BMT. Survival, leukaemia-free survival (LFS), incidence of transplant-related mortality, incidence of rejection and probability of relapse do not differ between the 117 SI+ and the 118 SI- patients at a median follow-up time of 2.5 years (minimum 0.5 years). LFS at 30 months is 56% (SE 5%) for the SI+ and 51% (SE 6%) for the SI- group (p = 0.65). LFS is better for younger patients (less than 25 years), for patients without T cell depletion and for those with a low white blood cell count at diagnosis (less than 30 x 10(9)/l) (p less than 0.05). It is worst for male recipients of a female marrow (p less than 0.05). The incidence of graft-versus-host disease grade greater than or equal to II was higher in the SI+ group, though not significantly. We conclude that routine splenic irradiation prior to BMT for patients with CML is of no benefit and should not be used as a routine procedure.
UNLABELLED: Patients with severe aplastic anemia (SAA; n = 46) were studied in long-term bone marrow culture (LTBMC) systems and compared with allogeneic marrow transplant (BMT) recipients (n = 16) (within 30 days following BMT) and normal control patients (n = 12). SAA patients were divided in two groups: transfusion-dependent (Tx-D) SAA patients (group A; n = 15) and transfusion-independent (Tx-I) patients after treatment with antilymphocyte globulin (group B; n = 31). Cultures were analyzed at three levels: stromal layer (SL) formation (score: 0, no SL; 1, half confluent SL; and 2, confluent SL), number of nucleated cells in suspension, and growth of CFU-GM colonies. SL formation was rapid and complete in SAA patients, groups A and B (mean score on day 14: 1.3 and 1.4), similar to controls (mean score on day 14: 1.3), whereas an impairment of SL formation was seen in BMT recipients (mean score on day 14: 1.0). The number of nucleated cells in suspension increased significantly on day 7 of culture in controls (7.6-fold), significantly more than in BMT and SAA patients, and declined thereafter. Colony formation was also significantly increased on day 7 in Tx-I SAA patients, BMT recipients, and normal controls (4-, 5-, and 16-fold, respectively), lasting respectively 2, 3, and 4 weeks. Increments of colony formation were also obtained in Tx-D SAA patients, but in the first week of culture only. IN CONCLUSION: 1) a significant impairment of SL formation was seen in BMT recipients, but not in SAA patients; 2) a significant increment of granulocyte-macrophage colony-forming units (CFU-GM) growth can be obtained in patients with marrow failure early after starting long-term culture; 3) the number of CFU-GM grown in these culture conditions from Tx-I SAA patients parallels the number of progenitors from early post-BMT recipients; and 4) progenitor cells from Tx-D SAA patients are not only reduced in numbers, but also exhibit a poor ability to survive in LTBMC.