Biomedical subjects
Publications and source records attributed to N Milpied.
A patient treated by recombinant human alpha interferon for chronic myeloid leukemia developed a T cell lymphoma. The T cell lymphoma cells were demonstrated to be genotypically different from the chronic myeloid leukemia cells. The possible role of interferon therapy in stimulating T cell proliferation is discussed.
The optimal source of stem cells is a controversial issue in the field of autologous stem cell transplantation. A comparison of autologous bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) after first remission induction treatment in multiple myeloma was made by a retrospective analysis of 132 transplants performed in 18 French Centers from 1984 to 1991 (81 autologous BMT, 51 PBSCT). The two groups differed in the median age (PBSCT 49 years; autologous BMT 55 years, P < 0.001), the duration of chemotherapy prior to transplantation, the interval between stem cell collection and transplantation, and in the conditioning regimen (more total body irradiation and higher doses of irradiation in the PBSCT group). The median time to neutrophil recovery was shorter in the PBSCT group (13 days vs. 20 days, P < 0.001), but the median time to platelet recovery did not differ significantly between PBSCT (26 days) and autologous BMT (22 days). There was no significant difference between the two groups regarding overall response rate (PBSCT 84%, autologous BMT 82%) and complete remission rate (PBSCT 37%, autologous BMT 36%). The actuarial relapse-free survival, time to treatment failure and overall survival were not significantly different. A case controlled study comparing 43 autologous BMT and 43 PBSCT matched for age and status at the time of transplantation did not show any advantage of PBSCT over autologous BMT in terms of immediate outcome, relapse-free survival, overall survival and time to treatment failure. Thus, in this retrospective analysis, the only significant benefit for PBSCT was reduced time to neutrophil recovery.
The aim of this prospective study of 162 recipients of bone marrow transplantation (BMT) was to evaluate the use of DNAemia detection by semi-nested PCR for the diagnosis of human cytomegalovirus (HCMV) infection and HCMV disease. We compared the results obtained for DNAemia with those obtained for viremia, using the shell vial assay. Patients were divided in three groups, according to BMT type (allogeneic or autologous) and date of transplant; 876 DNAemia/viremia pairs were analyzed and the overall concordance between the two tests was 97.5%. Discrepancies between the two tests were essentially due to the earlier positivity of DNAemia. Among the 10 patients with positive DNAemia episodes, 9 developed HCMV disease. DNAemia was more sensitive than viremia for HCMV disease diagnosis, while viremia had a higher positive predictive value. DNAemia appeared easily adaptable to routine laboratory use, less expensive and more informative than viremia. This study shows that DNAemia is a method that can replace viremia detection, allowing HCMV infection and disease follow-up of recipients of allogeneic BMT during the first year after BMT.
We previously demonstrated the potential of anti-IL-2R and anti-TNF alpha moAbs in the treatment of acute graft-versus-host disease (GVHD). However, one major problem was the recurrence of acute GVHD on treatment discontinuation. To target the two main effectors of acute GVHD lesions, T and NK cells on the one hand and TNF alpha on the other, we combined anti-CD2 and anti-TNF alpha moAbs. Then to prevent acute GVHD recurrence, we administered anti-IL-2R moAbs known for their inhibitory effect on activated cells. We included 15 patients with steroid-resistant acute GVHD. Seven were grafted from a genotypically-identical sibling, 5 from HLA-matched unrelated donors and 3 from partially-matched related donor. Prophylaxis of acute GVHD consisted of cyclosporin A +/- methotrexate or corticosteroids. Before treatment 6 patients had grade II, 2 patients grade III and 7 patients grade IV acute GVHD. Anti-TNF alpha (B-C7) moAbs (10 mg/day/4 days) were combined with anti-CD2 (B-E2) moAbs (10 mg/day/10 days) on the fifth day (day 5), anti-IL-2 receptor (B-B10) moAbs were given at 10 mg/day/10 days followed by 5 mg every other day for another 50 days. On day 15, 5 patients achieved a complete remission, 4 a very good partial response (62% a good response), 2 had a partial response and 4 did not respond. GVHD recurred in 4 of the 9 responders, although anti-IL-2R moAb treatment was maintained. Three patients are long-term survivors without chronic GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)
We recently demonstrated that frequencies of T cell receptor-V (TcR-V)-specific subsets are frequently altered after both allogeneic and autologous BMT. The data reported here describe several characteristics of altered T cell subsets: (i) their capacity to endure peripherally, (ii) their correspondence to clonal donor T cell subsets, (iii) the origin of the clone (in one case amenable to analysis) from a mature T cell and not from new lymphopoiesis, and (iv) the presence of such a clone throughout a year of follow-up in a patient with chronic graft-versus-host disease (GVHD) in whom it represented up to 1/10th of CD3+ peripheral blood lymphocytes (PBL) and was found to be host-reactive. Taken together, these findings provide direct evidence for the oligoclonality of a large proportion of the peripheral T cell repertoire in patients subsequent to bone marrow transplantation, possibly accounting for their frequent depressed immune status. Moreover, the anti-host reactivity demonstrated in a clone from the patient with chronic GVHD strongly suggests that an oligoclonal response can be linked to a pathological process.
BACKGROUND: High dose melphalan is used widely in the treatment of multiple myeloma (MM) and in the conditioning regimen of autologous stem cell transplantation (ABST). Double courses of high dose melphalan and double autologous bone marrow transplantation (ABMT) programs also have been widely reported. However, there are no data about the feasibility and efficacy of three courses of high dose therapy, such as high dose melphalan or powerful therapies in the treatment of malignant disease. METHODS: In 1991, a retrospective study in France was initiated to evaluate how many patients with MM had received three courses of high dose therapy with or without hematopoietic stem cell rescue. RESULTS: This small study of six patients with multiple myeloma showed that three courses of high dose therapy with or without stem cell rescue can be performed with relative safety. Stem cell rescue appears to shorten the duration of aplasia. In terms of antitumor response, long term response could be obtained in patients with MM that responded to the first course of high dose melphalan. CONCLUSIONS: High dose therapy with or without ABMT can be an effective treatment for relapse in a subgroup of patients with MM who respond to high dose melphalan as initial treatment.
A phase II study was undertaken to assess whether continuous infusion of high-dose recombinant interleukin-2 (rIL-2) alone was active against different histologic subtypes of heavily pretreated lymphoma. Sixty one lymphomas were included in the study. rIL-2 (Roussel UCLAF, Romainville, France) was administered by continuous infusion at 20 x 10(6) IU/m2 for three cycles of 5 days, 4 days, and 3 days, during the first week, third week, and fifth week, respectively. Twenty-four low-grade non-Hodgkin's lymphomas (NHL) were resistant to an anthracycline-containing regimen. Twenty-three intermediate and high-grade NHL were refractory to initial treatment or to salvage therapy. Seven Hodgkin's diseases were refractory to at least three regimens or relapsed after autologous bone marrow transplantation. Seven mycosis fungoides were refractory to chemotherapy. In low-grade NHL, one complete response (CR) was observed. In aggressive NHL, there were three CRs and two partial responses (PRs). No response was noted in Hodgkin's disease. One CR and four PRs were observed in mycosis fungoïdes. Complete response durations were 23, 20, 17, 12, and 4 months. Grade 4 toxicity was observed in 29 patients leading to arrest of therapy in 12 patients. The response to rIL-2 therapy in lymphoma differs according to histologic subtypes. Five responses were observed in 23 aggressive lymphomas. Five of seven mycosis fungoïdes responded; these preliminary results warrant testing of a larger number of patients.
Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). Our aim was to study the prophylactic effect of high-dose intravenous acyclovir given around the time of BMT followed by oral acyclovir on CMV infection and survival. 310 BMT recipients at risk of developing CMV infection were randomised to one of three regimens in a double-blind and double-dummy design: intravenous acylclovir (500 mg/m2, three times a day) for 1 month followed by oral acyclovir (800 mg four times a day for a further 6 months) (intravenous/oral group); intravenous acyclovir followed by oral placebo (intermediate group); or low-dose oral acyclovir (200 or 400 mg, four times a day) followed by placebo ("controls"). Analysis was by intention-to-treat. Intravenous acyclovir significantly reduced the probability of and delayed the onset of CMV infection. There was no further reduction in infection risk with the addition of long-term oral acyclovir. Time to CMV viraemia was delayed in the intravenous/oral acyclovir group compared with controls. Extending the prophylaxis with oral acyclovir significantly improved survival: 79 of 105 recipients were still alive at 7 months compared with 60 of 102 controls (p = 0.012). Although the intravenous/oral acyclovir group did significantly better than controls in terms of survival, the difference between the intravenous/oral acyclovir group and the intermediate group was of borderline statistical significance (p = 0.054). Adverse events that were possibly treatment related were similar in all three groups. The most commonly reported events were nausea, vomiting, elevated creatinine, and renal failure. High-dose intravenous followed by oral acyclovir improved survival and was of benefit in prophylaxis against the effects of CMV after BMT. Interpretation of CMV infection was made difficult because an intermediate treatment (intravenous acyclovir followed by oral placebo) was as effective as high-dose intravenous/oral acyclovir.
Haemopoietic growth factors are accepted as accelerating haemopoietic recovery after bone-marrow grafting, yet no large randomised trials have been published that convincingly show benefit. Lenograstim (glycosylated recombinant human granulocyte colony-stimulating factor) was given to 315 patients after bone-marrow transplantation in a prospective randomised placebo-controlled multicentre trial. 1 day after bone-marrow infusion, 163 patients received lenograstim 5 micrograms/kg per day by 30-min infusion, and 152 patients received placebo daily for 28 days or until neutrophil recovery. 137 patients had lymphoma, 35 myeloma, 85 acute lymphoblastic leukaemia, and 58 a solid tumour. Patients were stratified by age and by type of bone-marrow transplantation (BMT). Neutrophil recovery to above 10(9)/L for 3 consecutive days was seen earlier in lenograstim-treated patients (16 vs 27 days, p < 0.001). Time to neutrophil recovery above 0.5 x 10(9)/L was reduced (14 vs 20 days, p < 0.001). The difference was significant both in autograft (20 vs 14 days, p < 0.001) and allograft (20 vs 14 days, p < 0.01) patients, in children (20 vs 13 days, p < 0.001), and adults. Lenograstim-treated patients had fewer days of infection, and of antibiotic administration, and also spent less time in hospital. However, clinical and microbiological sepsis was similar in both groups. There was no significant toxicity ascribed to lenograstim. Survival was the same at days 100 and 365. In patients undergoing autologous or allogeneic BMT for neoplastic disease, lenograstim significantly reduced duration of neutropenia and led to earlier hospital discharge.
We developed two multidisciplinary tutorial programs (TOBRA-DIDACT and VANCO-DIDACT) for teaching the basic principles of antibiotic drug monitoring by simulation of repeated administrations to fictitious patients whose physio-pathologic characteristics were pre-defined in the programs. To illustrate the two types of bactericidal kinetics, we have chosen one time-dependent (vancomycin) and one concentration-dependent (tobramycin) antibiotic. These computer-assisted programs operate on an interactive mode. In each of them, three main steps are connected: (1) Various types of clinical cases are submitted to the student: for each of them, case report includes clinical characteristics, location of infection, bacterial strain and minimal bactericidal concentration. These data must be taken into account during the following steps. (2) The student has to establish the treatment schedule: route of administration, dose for each injection, intervals between injections and duration of infusion. (3) The result of the dosage scheme proposed by the student is represented by a simulation of plotting antibiotic plasma concentrations vs. time during the first 4 days of treatment. These curves are obtained by a monoexponential (TOBRA-DIDACT) or biexponential (VANCO-DIDACT) pharmacokinetic model. Peak and trough concentrations are calculated at steady-state. An expert system provides a commentary with each result to evaluate the efficacy of the treatment and to assist the student in improving his prescription. TOBRA-DIDACT and VANCO-DIDACT illustrate the influence of age, obesity, renal impairment, location of infection and bacterial strain on antibiotic therapy. They also show the role of route of administration, dosing and intervals between injections on therapeutic response.(ABSTRACT TRUNCATED AT 250 WORDS)
Vancomycin (V) is widely used in neutropenic patients, though its kinetics are known in this type of patient. In the present study, ten patients were included: all of them received an intensive therapy for non-Hodgkin malignant lymphoma, Hodgkin disease, myeloma, acute leukemia, followed by an autologous bone marrow transplantation in 6 cases. All patients were neutropenic (100/mm3). The pharmacokinetic study was done at the first V administration: 1000 mg V were injected as a 1-h infusion. Plasma V concentrations were measured by an enzyme immunoassay (EMIT, Syva, France). V maximal and minimal concentrations were 61.3 +/- 38.6 micrograms/ml and 1.69 +/- 0.77 microgram/ml, respectively. Total V clearance was 158 +/- 51 ml/min, with a creatinine clearance of 141.2 +/- 36.2 ml/min on test day. V plasma kinetics can be described by a biexponential model, with the following parameters: [table: see text] These data show a 3-fold increase of initial volume of distribution and a shortened (3-fold) T1/2 beta, if compared to values obtained in normal subjects. Because the bactericidal effect is time dependent, there can be a risk of insufficient antibiotic effect throughout the day. Our data suggest that new therapeutic regimens are needed for these patients.
The pharmacokinetics of vancomycin were studied in 10 neutropenic patients (4 male, 6 female) using the USC*PACK Clinical Programs. The experimental data was determined after the first administration of 1000 mg injected as a 1-h infusion. Eight blood samples were collected between 15 min and 11 h after the end of the infusion. Plasma vancomycin concentrations were measured by immunoassay procedure. Creatinine clearance and urine flow were also measured. Pharmacokinetic parameters were computed using a two-compartment model: Vc = 0.270665 +/- 0.161033 (l.kg-1); Kcp = 0.732927 +/- 0.464449 (h-1); Ks = 0.004952 +/- 0.00272 (min.ml-1.h-1); Kpc = 0.470243 +/- 0.194677 (h-1); Ki = 0.011675 +/- 0.004086 (h-1); Ke = 0.644415 +/- 0.239376 (h-1). When we compared this population to the general population of the program, Ke was increased. Elimination constant Ke was not correlated to either creatinine clearance or urine flow. Evaluation of the predictive performance of the Bayesian PC Program for adaptive control of vancomycin therapy in neutropenic patients is the next step of this study.
G-CSF (5 mg/kg/day Filgrastim) was administered from day 7 after autologous bone marrow transplantation (ABMT) in a series of 17 patients treated for multiple myeloma or non-Hodgkin's lymphoma. In comparison with retrospective controls receiving ABMT without G-CSF and matched for age, underlying disease, disease status at ABMT, number of CFU-GM/kg reinfused, conditioning regimen and number and type of chemotherapy courses prior to ABMT, the duration of neutropenia, intravenous antibiotics and hospitalization was significantly reduced in the G-CSF group (p < 0.001). Delaying the administration of G-CSF after ABMT is an interesting possibility which merits further exploration in prospective randomized studies.
The optimal treatment of post-transplantation lymphoma remains undefined. We report a case of high grade lymphoma occurring after a renal transplant treated with high-dose chemotherapy and ABMT leading to a 10 month CR. Relapse occurred 8 months after reintroduction of CsA, which may have been implicated in this relapse.
To increase the cure rate of advanced hematologic malignancies following allogeneic bone marrow transplantation we sequentially evaluated two intensified conditioning regimens. Eleven patients with acute myeloblastic leukemia (AML) beyond the first complete remission or chronic myelogenous leukemia (CML) not in first chronic phase received an association of 13.5 Gy of fractionated total body irradiation (TBI) followed by cyclophosphamide (CY) 120 mg/kg. Following this regimen, the probability of relapse was 47% at 3 years and the non-relapse mortality rate was 27%. Given the acceptable tolerance of this regimen, 13.5 Gy fractionated TBI was associated with intensified chemotherapy consisting of a combination of CY 120 mg/kg, carmustine 300 mg/m2 and etoposide 600 mg/m2 (CBV). This regimen was administered to 22 patients with comparable diseases. Of these patients, 7 received a transplant from a matched unrelated donor and 2 other patients received a second transplant from the original genoidentical donor. For 15 patients with a genoidentical donor, including the 2 second transplant, the 3 year probability of survival, disease-free survival and relapse are 40%, 40% and 14%, respectively. No regimen-related toxic deaths were recorded during the first 100 days. Of 7 patients with matched unrelated donors, 3 died before day 100, one death being directly attributable to the regimen. Early non-fatal regimen-related toxicity consisted mainly in grade II mucositis with no grade III or IV toxicity in recipients of genoidentical marrow. The late deaths were mainly due to chronic GVH-related complications. In conclusion, the association of fractionated 13.5 Gy TBI and CBV carries a high antileukemic activity and an acceptable toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Patients with stage IV high/intermediate grade cutaneous non-epidermotropic lymphoma of skin as first localization of the disease have a poor prognosis. In this setting, autologous bone marrow transplantation (BMT) has rarely been evaluated. We report here on the treatment of four patients with such lymphomas with autologous BMT using 12 Gy total body irradiation (TBI) and CBV (cyclophosphamide, carmustine and etoposide). Using a plexiglass screen, TBI delivered an homogenized dose to the skin. With this conditioning regimen, all patients are still in complete remission 22, 44, 46 and 51, respectively, months after high-dose chemotherapy, TBI and autologous BMT.
We investigated T cell receptor (TCR) alpha/beta and gamma/delta repertoire reconstitution after autologous and allogeneic bone marrow transplantation (BMT) in humans using 13 monoclonal antibodies directed at constant and variable regions of the TCR. The TCR gamma/delta repertoire was studied kinetically during the first month and then 1 year post-BMT whereas alpha/beta peripheral blood T lymphocytes (PBTL) were studied within the first 3 months and 1 year post-BMT. Through these two studies, we found 7 of 26 patients with over-represented TCR gamma/delta subsets during the early period post-BMT. Moreover, during this period the V gamma 9V delta 2 frequency among gamma/delta T cells was found to be higher than among normal donors. Study on TCR alpha/beta T cells also revealed abnormally expanded V-specific subset (5 of 10 patients within 3 months following BMT) demonstrating that repertoire alteration early after BMT is a general phenomenon concerning potentially all T cell subsets. More surprisingly, the alpha/beta T cell repertoire was also found to be altered late after BMT (7 of 15 patients after 1 year post-BMT presented one or more overepresented alpha/beta TCR subset). These alterations of TCR combinatorial diversity should be taken into account in understanding the immunological status of patients after BMT.
The value of high-dose chemotherapy with hematologic stem cell rescue has not been established in the treatment of low-grade non-Hodgkin's lymphoma. We report the results of a retrospective 'France Autogreffe' study of 42 patients grafted in first partial remission (n = 13) or chemosensitive relapse (n = 29) for follicular lymphoma before January 1990. The median age was 38 years (range 26-61 years). Preparative therapy was chemotherapy alone in 22 patients and total body irradiation (TBI)-containing regimens in 20 patients. Thirty-seven patients received hematopoietic marrow stem cells. Bone marrow purging was performed in 15 patients. Five patients received peripheral blood stem cells. Three patients died of bone marrow transplantation toxicity and two others died in complete remission 10 months after autologous bone marrow transplantation. With a median follow-up of 43 months, relapse-free survival is 60%, event-free survival 58% and overall survival 83%. To date no prognostic factors have been shown.