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Biomedical subjects

D Maraninchi

Publications and source records attributed to D Maraninchi.

At least 127 records · Page 7Linked to original sources

Allogeneic bone marrow transplantation remains an efficient consolidation for adults with acute myeloid leukemia even when performed very soon after diagnosis (< 100 days). The SFGM (Société Française de Greffe de Moelle.

Allogeneic BMT is presently recognized as one of the reference anti-leukemic treatments for AML patients. It could be a very useful therapy in CR1 AML if it is efficient as an early form of consolidation after induction therapy. Later procedures may be of lesser importance since they concern a population which may have already been cured by chemotherapy. Alternatively it is not solved if very early BMT gives patients sufficient therapy and provides lower toxicity. To answer this question we analyzed data from the Société Française de Greffe de Moelle (SFGM) on a sub-group of patients according to the following criteria: (1) Allogeneic BMT carried out on patients with AML in CR1; (2) after January 1985; (3) conditioning with CyTBI; (4) GVHD prophylaxis with MTX-CsA; (5) interval between diagnosis and BMT < 100 days. Forty-two fulfilled all criteria. Age was 31 +/- 8 years and M/F ratio was 19/23. WBC at diagnosis were 36 +/- 49 x 10(9)/l and four patients needed two induction courses to achieve CR1. Median follow-up is now 51 (24-116) months. Twenty-two patients developed a grade > or = 2 acute GVHD. Early transplant mortality at 1 year is no higher than 14%. Two patients died of secondary malignancies at 3.5 and 6.5 years after BMT. Finally 5-year (and 7-year) probabilities for relapse, survival, leukemia and event-free survival are respectively 17% (17%), 71% (62%), and 71% (71%) and 68% (59%). These data indicate the feasibility of such an approach with low mortality and low relapse rates providing a good long-term outcome. This should prompt an invitation to initiate the search for an HLA-identical sibling when AML is diagnosed in a young patient eligible for allo-BMT.

Adult↗

Long-term side-effects in children receiving allogeneic bone marrow transplantation in first complete remission of acute leukaemia.

We evaluated the long-term side-effects of allogeneic BMT performed early in the course of childhood acute leukaemia (first complete remission and interval between diagnosis and BMT not exceeding 6 months). Thirteen patients fulfilled these criteria. Conditioning regimens included TBI in eight cases. Evaluation of growth and pubertal development, ophthalmological examination, assessment of thyroid, cardiac and pulmonary functions were performed. Neuropsychological evaluation included IQ score, memory tests and cranial MRI. Median follow-up after BMT was 5 years (range 2-10 years). Growth was normal in seven patients. Six patients experienced a decrease in SD score for height (range -0.1 to -1.9). Four children were evaluable for puberty: pubertal development was normal in three children and delayed in one case. Thyroid and left ventricular function were normal in all cases. Three patients had mild abnormalities of pulmonary function. In two patients cataracts were noted 7 and 10 years after fTBI. Mean full-scale IQ score was 102. Memory tests, performed in 12 cases, were in the normal range for 11 patients. In our study, frequency and severity of long-term side-effects following BMT for leukemia appeared lower than usually reported. A possible explanation is that children were transplanted very early in the course of their disease with neither cranial irradiation nor long exposure to chemotherapy prior to transplant.

Acute Disease↗

[Experience with other tumors: breast, ovary, brain tumors and sarcomas].

High-dose chemotherapy and autologous bone-marrow was widely tested in different solid tumors. This treatment is under investigation in metastatic and high-risk loco-regional breast cancer in France (Pegase protocol). There is few evidence of a role of high-dose chemotherapy in the first line treatment of poor-risk germ cell tumors. However the role of high-dose chemotherapy in the salvage setting of germ tumors is studied in an european randomized trial. At present there is no evidence of the role of this treatment in other solid tumors of adulthood.

Antineoplastic Agents↗

Comparison of anxiety, pain and discomfort in two procedures of hematopoietic stem cell collection: leukacytapheresis and bone marrow harvest.

The aim of this study was to compare anxiety, pain and discomfort of cancer patients submitted to either peripheral blood progenitor cell collection (PBPCC) or bone marrow harvest (BMH). Patients, randomized (7/1993-2/1994), in view of autograft, to receive the first procedure or the second one, completed self-administered questionnaires. Anxiety was assessed by the State Trait Anxiety Inventory and pain using visual analogical scale (VAS) and McGill Pain questionnaire. Before the procedure, BMH patients (n = 25) experienced more anxiety (P < 0.01) and more trouble or inconvenience for having to come and stay at the hospital (P < 0.0001) than PBPCC patients (n = 40). Pain due to BMH is significantly higher than pain induced by PBPCC (P < 0.001 for VAS and total McGill score). However, patients submitted to PBPCC with a femoral catheter (n = 19) had significantly higher total McGill scores and sensory sub-scores than patients without it (n = 21). At discharge from the hospital, PBPCC patients expressed more positive judgements towards the collection procedure than BMH patients. These results suggest that a better patient acceptability of high-dose chemotherapy followed by autograft may be obtained by substituting PBPCC for BMH for stem cell collection.

Adult↗

Ex vivo expansion of human peripheral blood progenitors.

Culture of human hematopoietic progenitors on a large scale could lead to several clinical applications within the near future, including the production of differentiated and functional cells, the increase in the number of early progenitors, especially stem cells, with such use as gene transfer, or the improvement of grafts used to limit the hematological toxicity associated with high-dose chemotherapy. In this case, one can still distinguish different objectives: improvement of grafts that contain low numbers of progenitors because of prior chemotherapies or because of marrow involvement for example, and qualitative changes in the graft content that would allow to envision the disappearance, or the further reduction, in the duration of absolute neutropenia that follows delivery of high dose chemotherapy ("nadir rescue"), despite substitution of mobilized blood cells to marrow cells and the in vivo use of hematopoietic growth factors. Additional advantages may be related to tumor purging in autologous expanded cells, and to the change in the ratio between hematopoietic progenitors and immunocompetent cells in allogeneic expanded populations. Therefore it appears that in vitro expansion currently raises two types of questions: the first ones are related to the definition of clinical or biological endpoints to be achieved, the second ones are related to "bioengineering", and deal with the efficiency and safety of progenitor cell cultures to be used for clinical applications. We here present preliminary results preparing future pilot clinical studies with ex vivo cultured human hematopoietic cells.

Antigens, CD↗

Interleukin-2 treatment in lymphoma: a phase II multicenter study.

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.

Adult↗

In vivo stimulation of neutrophil function by lenograstim (glycosylated rHuG-CSF) in oncohematologic patients: results of a phase I trial.

The aim of this work was to study the evolution of neutrophil functions in non-neutropenic cancer patients. Thirty non-neutropenic patients, median age 35 years (range 19-52), with solid tumors (n = 21) or lymphomas (n = 9) entered a phase I study of five days of s.c. (n = 24) or i.v. bolus (n = 6) lenograstim, recombinant human glycosylated granulocyte colony-stimulating factor (rHuG-CSF Chugai-Rhône-Poulenc), with dose escalation from 1 to 40 micrograms/kg/day. Neutrophil functions were studied before lenograstim (D1) and 24 h after the last dose (D6). Granulocyte count rose in a significant way, and enzyme release, phagocytosis and bacterial killing were stimulated. All patients had improvement of at least one neutrophil function. Directed migration was depressed, although it was still in the normal range. These findings confirm that lenograstim is a potent activator of neutrophil functions in non-neutropenic cancer patients and may be useful as an adjunct to conventional antimicrobial therapy.

Adult↗

Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia.

PURPOSE: Optimal postremission therapy remains controversial in adult patients with acute lymphoblastic leukemia (ALL). In a large multicentric trial (LALA87), we compared allogeneic bone marrow transplantation (BMT) with other postremission therapies (chemotherapy or autologous transplantation) using the result of the human leukocyte antigen (HLA) typing as a random allocation. PATIENTS AND METHODS: Patient eligibility requirements were as follows: (1) inclusion in LALA87 trial, (2) complete response to induction or salvage therapy, (3) age 15 to 40 years, and (4) at least one potential sibling donor. Patients with an HLA-identical sibling were assigned to the BMT group, while patients without a sibling donor constituted the control group. Allogeneic transplantation was scheduled for patients in the BMT group; in the control group, patients were randomly allocated to receive chemotherapy or autologous transplantation. RESULTS: Of 284 eligible points, 257 entered the study: 116 were allocated to the BMT group and 141 to the control group. The 5-year survival rates were not statistically significantly different between the two groups. When only patients with high-risk ALL were considered (those with [1] Philadelphia chromosome [Ph1] ALL, [2] null or undifferentiated ALL, or [3] c-ALL with either age greater than 35 years or WBC count > 30 x 10(9)/L or time to achieve complete remission > 4 weeks), overall survival (P = .03) and disease-free-survival (P = .01) were better for the BMT group compared with the control group (5-year overall survival rates, 44% v 20%; 5-year disease-free survival rates, 39% v 14%). CONCLUSION: Allogeneic transplantation does not improve survival in patients with standard-risk ALL and should be recommended only for patients with adverse prognostic factors.

Adolescent↗

Phase I study of in vivo lenograstim (rHuG-CSF) for stem cell collection demonstrates improved neutrophil recovery after autologous bone marrow transplantation.

Colony stimulating factors and especially rHuG-GSF, the first available neutrophil growth factor, have led to considerable interest in the field of stem cell transplantation because of their ability to induce stem cell peripheralization either alone or in association with high-dose chemotherapy. Few data exist, however, on the impact of rHuG-CSF on large scale bone marrow collection and autologous bone marrow transplantation (ABMT). This phase I, non-randomized, dose escalation study of rHu-G-CSF (lenograstim) administered to 30 patients at doses ranging from 1 to 40 micrograms/kg/day for 5 days before bone marrow harvesting showed that priming with rHu-G-CSF in vivo increased the number of bone marrow cells and D14 myeloid restricted progenitors (CFU-GM) and led to a better neutrophil recovery after ABMT compared with a contemporary unprimed control population. Otherwise, this study established that 5 days of rHuG-CSF therapy, as a sole stimulus, induced a tenfold increase in the circulating CFU-GM amongst which immature progenitors, estimated by the Delta assay (secondary CFU-GM grown after 7 days of liquid culture/primary CFU-GM), are detected. These conclusions were valid for doses as low as 2 micrograms/kg/day which induced only mild neutrophilia up to the highest dose (40 micrograms/kg/day) and suggest that a short course of rHuG-CSF is beneficial in increasing the stem cell collection.

Adolescent↗

[Why use chemotherapy in cancer of the bladder? What are the initial limitations].

Four chemical agents are active, in isolation, against metastatic bladder cancer: cisplatin (nephrotoxicity) (C or Cis), doxorubicin (cardiac toxicity) or adriamycin (A), vinblastine (V) and methotrexate (M). Combinations of these drugs are more effective, with complete response rates of up to 30 to 40%. The current combinations are: CM; Cis cyclophosphamide, A; CMV; MVAC. This last combination appears to be the most effective. Chemotherapy is essentially prescribed for palliative purposes (improvement of symptoms) in metastatic cancers. It may also constitute adjuvant treatment following total cystectomy, in order to decrease the local or distant recurrence rate. Neoadjuvant chemotherapy, before surgery, can reduce the tumour bulk allowing preservation of the bladder. Haematopoietic growth factors are used to reduce the toxicity of chemotherapy and the action of these drugs can also be potentiated by radiotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

Comparison of G-CSF-primed peripheral blood progenitor cells and bone marrow auto transplantation: clinical assessment and cost-effectiveness.

The introduction of hematopoietic growth factors (HGFs) offers new opportunities for autologous transplantation by facilitating and enriching collection of circulating progenitor cells from peripheral blood as a source of stem cell rescue. Substitution of peripheral blood progenitor cells (PBPC) from bone marrow in autologous transplantation for therapy in advanced cancers requires clinical and economic assessment. We carried out the first clinical and cost-effectiveness study in an experimental group of 16 patients autografted with PBPC primed by G-CSF alone and with G-CSF stimulation post-transplantation, comparing these with two other groups of 17 and 21 patients who received autologous bone marrow transplantation with and without G-CSF stimulation, respectively, post-transplantation. We confirmed the ability of primed PBPC to achieve durable engraftment in a shorter time than classical BMT (median number of days to reach 0.5 x 10(9)/l neutrophils = 10.5 versus 12 and 16, respectively) to improve overall hematological recovery (median number of days to recover a platelet count > or = 25 x 10(9)/l, independent of platelet transfusion = 14.5 vs 23 and 20) and to shorten length of hospitalization. Total costs of PBPC autografting remain lower than those of autologous BMT either with or without G-CSF, and cost-effectiveness ratios using hematological recovery end points are in favour of PBPC. Finally, PBPC is a safe and effective way of performing dose-intensification in cancer patients, although further improvements are required to optimize the procedure and so further decrease the costs.

Adult↗

Modifications of leukemic blast cells induced by in vivo high-dose recombinant interleukin-2.

High-dose recombinant human Interleukin-2 was given to 21 patients with acute myeloid (n = 11) or lymphoid (n = 10) leukemia in relapse. A rapid decrease in the peripheral leukemic blasts numbers was observed in six patients. We were unable to demonstrate at the bone marrow level a diminution in the percentage of leukemic blasts. However an increase in the expression of the adhesion molecule CD54/ICAM-1(LFA-1 ligand) affected the leukemic bone marrow blasts of these six patients. This increase in CD54 was found in eight of the 11 (73%) AML and four out of the ten (40%) ALL blasts and CD58/LFA-3 (CD2 ligand) to a lesser extent. This increased expression was not associated with modifications in the expression of MHC class II molecules. In vivo IL-2 also dramatically modified the bone marrow T-cell subsets via the increase of CD3+ cells expressing the CD45RO 'memory' marker (six out of the eight tested patients) or CD54 (seven out of the eight tested patients). Altogether these results demonstrate that leukemic blasts can be affected by in vivo IL-2 via mechanisms that could involve T cells.

Acute Disease↗

Reconstitution of human immunoglobulin VH repertoire after bone marrow transplantation mimics B-cell ontogeny.

Reconstitution of the human Ig repertoire after allogeneic and autologous bone marrow transplantation (BMT) was followed by analysis of the expression of the six VH families using in situ hybridization on BM cells at 30, 60, and 90 days postgraft. Our results indicate that during the early post-transplantation period, the expressed repertoire of VH is dramatically affected: VH3, the major expressed family in adult B cells, is decreased two- to threefold and is compensated by transient overexpression of the other families, especially VH4, VH5, and VH6. Similar results were observed in allogeneic and autologous grafted patients. Kinetics of reconstitution mimics normal repertoire development described in ontogeny, although normalization, as compared with the adult pattern, may take as long as 1 year.

Adult↗

[Hematopoietic growth factors].

Haematopoietic growth factors are a family of genetically determined low molecular weight glycoproteins which regulate the proliferation and differentiation of haemopoietic cells through specific membrane receptors. GCSF and GMCSF reduce the morbidity from infections associated with the neutropenia induced by chemotherapy of onco-haematological neoplasia; EPQ totally corrects not only the anaemia of patients with chronic renal failure, but also 50 percent of anaemias related to chemotherapy; finally, the activity of IL 3 on platelet production seems to control the thrombocytopenia which restricts the use of therapeutics.

Erythropoietin↗