Cost-effectiveness of repeated aphereses in poor mobilizers undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation.
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Adult↗
Biomedical subjects
N Vey
Publications and source records attributed to N Vey.
Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis.
Large granular lymphocyte (LGL) proliferation typically follows a chronic course during which major features are cytopenia and immune abnormalities. Elevated numbers of LGL were reported in a few cases following allogeneic stem cell transplantation (allo-SCT). In this report, we present a retrospective analysis of LGL cases that occurred following allo-SCT in a cohort of 201 consecutive patients transplanted over a period of 7 years. Six cases were identified and LGL expansion occurred more frequently following a reduced fludarabine and anti-T lymphocyte globulin-based preparative regimen (4 cases/49), than after a conventional myeloablative regimen (2 cases/152). Expansion of LGL was seen between 3 and 15 months following allo-SCT. Hematopoiesis, with mild to severe cytopenia, was a favored target for LGL. Autoimmune manifestations including polyarthritis and hypergammaglobulinemia were also observed. LGL proliferation was observed in the context of chronic antigenic stimulation associated with recurrent viral infections especially CMV. Moreover, five out of these six high risk patients achieved a long-term complete remission concomitant or following LGL expansion. These data suggest that LGL might be a subset of effector lymphocytes which may participate to the graft-versus-tumor effect.
Adult↗
Recovery of lymphocyte and dendritic cell subsets following reduced intensity allogeneic bone marrow transplantation.
Approaches using reduced conditioning regimens have been developed to obtain minimal procedure-related toxicity. Such novel therapeutic options are being explored with good preliminary results concerning feasibility and engraftment. However, many aspects remain under-evaluated and few data are available about immune and dendritic cell (DC) reconstitution after these highly immunosuppressive regimens. We present here our data in 20 patients receiving allogeneic bone marrow transplantation (allo-BMT) using a reduced preparative regimen. We evaluated in the first 3 months following allo-BMT, several immunological parameters including DC subsets, and compared these to historical results obtained in a group of myeloablative allo-BMT patients. We found an early recovery of leukocytes, CD8+ and NK lymphocytes. We also found a trend towards an improved B cell recovery. These results are somewhat in contrast to the altered immune recovery observed in the myeloablative setting. In addition, we found a significant early circulating DC recovery. Circulating blood DCs were also found to be of full donor origin as assessed by FISH in sex-mismatched pairs. Nevertheless, naive CD4 + CD45RA + T cells were found to be profoundly reduced following such regimens.Collectively, these data further enhance the overall benefits of reduced intensity regimens and the need for a stringent biological monitoring for assessment of the potential advantages of reduced intensity allo-BMT in comparison with conventional allo-BMT.
Adult↗
Large granular lymphocytes (LGL) following non-myeloablative allogeneic bone marrow transplantation: a case report.
We report here the first case of large granular lymphocytes (LGL) expansion following non-myeloablative allo-BMT for chronic myeloid leukemia. We characterized the morphologic, phenotypic and functional features of the LGL subset amplified in vivo 14 months after allo-BMT. Our results indicate that LGL can mediate in vitro a cytolytic activity on tumor cells. In vivo, the timing of the LGL expansion was associated with a sustained complete molecular remission. These observations suggest that LGL are a subset with the properties of effector lymphocytes which may contribute to the graft-versus-tumor effect.
Bone Marrow Transplantation↗
Simultaneous occurrence of kaposi's sarcoma and chronic myelogenous leukemia.
We report here a 75-year-old man from South France who developed Kaposi's Sarcoma (KS) 5 months after diagnosis of Philadelphia-chromosome positive chronic myelogenous leukemia (CML). He was found positive for HHV-8 by PCR, negative for both HIV 1 and HIV 2 by serology, and had a normal CD4/CD8 ratio. Favourable evolution of both CML and KS has been obtained with vinblastine and interferon alpha treatment. The patient is currently alive in complete remission of SK and major cytogenetic remission of CML with a 48 month follow-up. Since no immune deficiency could be documented in the patient, this rare observation suggests that CML may have triggered the onset of SK through cytokine release.
Aged↗
Lymphomatoid papulosis associated with both severe hypereosinophilic syndrome and CD30 positive large T-cell lymphoma.
BACKGROUND: Previous reports have found an association between lymphomatoid papulosis and hypereosinophilic syndrome, as well as lymphomatoid papulosis and lymphoma. In the current study the authors report what to their knowledge is the first reported case of these three diseases occurring simultaneously in the same patient. METHODS: The authors followed the clinical course of a 64-year-old man with lymphomatoid papulosis associated with severe hypereosinophilic syndrome complicated by involvement of the lungs and heart. RESULTS: After 6 years of follow-up, the patient developped a large T-cell, CD30 positive lymphoma. The bone marrow biopsy was typical of hypereosinophilic syndrome associated with fibrosis, with focal lymphomatous infiltrates comprised of large cells resembling the type A cells of lymphomatoid papulosis. Complete remission of the lymphoma was obtained with chemotherapy. CONCLUSIONS: This exceptional case report suggests a link between the three diseases. Lymphomatoid papulosis belongs to the spectrum of CD30 positive lymphoproliferative disorders and CD30 positive lymphocytes of lymphomatoid papulosis are known to have a Th2 profile with possible secretion of eosinopoietic cytokines.
Bone Marrow Cells↗
Rescue of haemopoiesis by a combination of growth factors including stem-cell factor.
We observed an unexpectedly rapid rise in platelet counts with complete haematological recovery after a BEAM regimen, in a patient who could not be rescued by autologous transplant but who received filgrastim, epoetin alfa, and ancestim. We feel that these results may be attributed to this specific growth factor combination, including ancestim, a cytokine known to act on primitive stem cells. If confirmed, this observation may open new possibilities in intensive chemotherapy for patients for whom haematopoietic progenitors are difficult to harvest. This may also represent an alternative to ex-vivo expansion and deserves further investigation.
Adult↗
High rate of secondary viral and bacterial infections in patients undergoing allogeneic bone marrow mini-transplantation.
New approaches using nonmyeloablative-conditioning regimens have been developed to cause minimal procedure-related toxicity. Such novel therapeutic options are being explored with good preliminary results concerning feasibility and engraftment. However many aspects remain under-evaluated, and few data are available about viral and nonviral infections after these highly immunosuppressive regimens. We present our preliminary data on 21 patients receiving a highly immunosuppressive conditioning strategy, focusing on early infectious complications. Early viral infections before day 45, especially CMV, occurred at a high rate (65%). Furthermore, 33% of patients presented with late bacterial infections (predominately gram negative) although they were not neutropenic compared to conventional conditioning regimens. Although there is presently real interest in these new conditioning regimens which result in reduced immediate transplant-related mortality, it is important that investigators be aware of these pitfalls which may secondarily increase transplant toxicity. Further studies are needed to confirm these findings.
Adult↗
CD34(+) immunoselected cells for poor graft function following allogeneic BMT.
BACKGROUND: Poor graft function without signs of graft rejection following allogeneic BMT (allo-BMT) occurs in around 9% of patients. A high incidence of hazardous complications may be encountered, leading to life-threatening situations. METHODS: We describe three patients who underwent allo-BMT for acute leukemia in first complete remission and untreated myelodysplastic syndrome. The three patients experienced prolonged and profound granulocytopenia, anemia and thrombocytopenia, despite growth factors and transfusions. This was not corrected by donor leukocytes infusion. They received a boost of CD34(+) positively-selected cells from their HLA-identical sibling donors. RESULTS: A rapid improvement of peripheral blood cell counts was observed in both patients who were in full donor chimerism status at time of boost infusion, whereas the patient with mixed chimerism did not show any signs of improvement. Neither patient suffered further exacerbation of GvHD. DISCUSSION: Allogeneic positively-immunoselected CD34(+) cells can represent an interesting alternative treatment for poor graft function following allo-BMT, in the absence of graft rejection signs.
Adult↗
The topoisomerase I inhibitor DX-8951f is active in a severe combined immunodeficient mouse model of human acute myelogenous leukemia.
The severe combined immunodeficient (SCID) mouse model of human acute myelogenous leukemia (AML) is a unique system for preclinical in vivo evaluation of the activity and toxicity of new agents. The topoisomerase I (topo I) inhibitor topotecan is active in patients with AML and myelodysplastic syndromes. DX-8951f is a novel topo I inhibitor with more potent antitumor effects than topotecan or CPT-11 in vitro. To study the in vivo activity of DX-8951f, 6-week-old female SCID mice received injections into the tail vein with 2 x 10(7) exponentially growing KBM-3 cells. In each experiment, three to five sets of five mice were treated with DX-8951f doses ranging from 7.5 to 80 mg/kg and at schedules of 1, 3, and 5 days; a control set of five mice was treated with the drug vehicle alone. One group received DX-8951f on day 7 of the inoculation with KBM-3 (early-treatment group). To study the activity of DX-8951f in advanced disease, a second group was treated 1 month after the inoculation, when the animals were developing symptoms (late-treatment group). The study end point was the duration of survival until death from leukemia, which was assessed clinically and by the presence of the human DQ alpha gene in tissue samples by PCR. Six experiments were conducted with 170 animals. Survival was higher in both the early- and late-treatment groups than in untreated controls, and the treated groups had significantly less central nervous system disease. Significantly improved survival was observed in animals treated early with 60 and 80 mg/kg as a single injection, with 15 and 20 mg/kg over 3 days, and with 7.5 and 10 mg/kg over 5 days. In the late-disease model (treatment starting on days 28-35), improved survival was observed with a single dose of 80 or 20 mg/kg over 5 days. Dose escalation was limited by dilution problems at the 1-day schedule and by toxicity (mainly gastrointestinal) of the prolonged schedules. Both efficacy and toxicity were dose schedule dependent, increasing with higher doses and prolonged exposure. By establishing the antileukemic activity of DX-8951f against human AML transplanted into SCID mice at doses below the LD10, our data provide a rationale for clinical evaluation of the drug in patients with AML and favor the use of prolonged administration.
Animals↗
Effect of complete remission on survival in patients with acute myelogenous leukemia receiving first salvage therapy.
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Antineoplastic Combined Chemotherapy Protocols↗
Positive selection of CD34+ peripheral blood progenitor cells in patients with low-grade lymphoid malignancies and bone marrow involvement.
PURPOSE: 16 patients with low-grade lymphoid malignancies and bone marrow involvement were transplanted with selected CD34 positive Peripheral Blood Progenitor Cell (PBSC) prepared from autologous aphereses. PATIENT AND METHODS: All but one patients were mobilized with a combination of chemotherapy (including high-dose cyclophosphamide and VP16 or adriamycin, aracytin with cysplatyl) and recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF). RESULTS: A median of 3 (range, 1 to 9) aphereses yielded 15.35 x 10(6) CD34+ cells/kg (range, 4.45 to 70.88). A median of 5.01 x 10(6) adsorbed CD34+ cells/kg (range 2.01 to 24.13) was obtained after selection (median purity: 86%; range, 59-99%). The CD34 PBSC were infused one day after either one of two conditioning regimens: 11 patients received the association of cyclophosphamide (120 mg/kg) and TBI (8Gy), and 5 patients received the BEAM regimen. No recombinant hematopoietic growth factor was used after cell reinfusion. Median days to 0.5 x 10(9)/l neutrophils and 50 x 10(9)/l platelets were 13 (range, 9 to 18) and 16 (range, 11 to 35), respectively. The median number of red blood cell (RBC) unit transfusions was 4 (range, 0 to 10). The median number of platelet transfusions was 3.5 (range, 0 to 8). No individual received backup PBSC, nor required platelet transfusion beyond 3 months post-transplant. CONCLUSION: This study confirms the feasability of using blood CD34 cells to support hematopoietic recovery after myelo-suppressive or myelo-ablative regimens, in patients with low-grade NHL.
Adult↗
Combination of topotecan with cytarabine or etoposide in patients with refractory or relapsed acute myeloid leukemia: results of a randomized phase I/II study.
The topoisomerase I inhibitor topotecan has shown activity in acute myeloid leukemia (AML) and myelodysplastic syndromes. The present study was designed to assess whether topotecan with cytosine arabinoside (ara-C) or with etoposide (VP-16) should be studied in phase II trials in patients with refractory or relapsed AML. Patients with refractory or relapsed AML were assigned to one of 3 strata defined by expected CR rates of 7%, 20% and 40%, then randomly assigned to receive topotecan (dl-5) and ara-C (1 g/m2 over 2 hours; dl-5), topotecan (d1-5) followed by VP-16 (250 mg/m2 twice daily, d6-7), or VP-16 (250 mg/m2 twice daily dl-2) followed by topotecan (d3-d7). A dose-finding phase was conducted in the poorest stratum of each arm (topotecan starting dose: 1.0 mg/m2/day x 5). A Bayesian pre-phase II selection design was used to assess whether the CR rate with a given arm was sufficient to merit investigation in phase II. Thirty-seven patients, median age 58 years, were treated. Their median first CR duration was 28 weeks and 24% were primary refractory. Grade 3-4 mucositis occurred in the initial patients in the topotecan --> VP-16, but not in the topotecan + ara-C or VP-16 --> topotecan arms. Consequently, in subsequent patients, the topotecan dose was lower in the topotecan --> VP-16 than in the other 2 arms (1.0 vs 1.25 mg/m2 daily x 5) and the VP-16 dose was lower in the topotecan --> VP-16 arm (200 vs 250 mg/m2 twice daily x 2). One CR occurred (topotecan --> VP-16 arm), and the treatment arms were terminated after 10, 15, and 12 patients were treated on the topotecan + ara-C, topotecan --> VP-16, and VP-16 --> topotecan arms, respectively. The principal cause of failure was insufficient anti-leukemia effect rather than death on study, and toxicity was minimal at the final doses used. We concluded that none of the combinations studied here warrants phase II evaluation in very poor prognosis AML salvage patients.
Adolescent↗
Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation in patients with refractory or relapsed acute leukemia.
PURPOSE: Topoisomerase I inhibitors have shown promising anti leukemic activity in acute myelogenous leukemia (AML) and myelodysplastic syndrome. In this phase I study, we investigated the toxicity profile, pharmacokinetics, and activity of a prolonged continuous infusion schedule of the colloidal dispersion formulation of 9-amino-camptothecin (9-AC/CD) in patients with acute leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed AML, acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia in blastic phase (CML-BP) were included in the study. Eligibility criteria were age greater than 15 years, performance status of 2 or better, creatinine < 1.5 mg/dl, and bilirubin < 1.5 mg/dl. 9-AC/CD was given as a continuous intravenous infusion over seven days every three to four weeks. The starting dose was 0.2 mg/m2/d (1.4 mg/m2/course). Courses were given every three to four weeks according to toxicity and anti leukemic efficacy. This phase I study used the classical 3 + 3 design. The dose was escalated by 50% until grade I toxicity was observed, and then by 30% to 35% until the dose limiting toxicity was defined. At the maximal tolerated dose (MTD), 8 to 10 patients were planned to be treated to better define the toxicity and early-activity profiles. RESULTS: Thirty-nine patients (AML thirty-six patients; ALL two patients; CML-BP one patient), median age 56 years, were treated. Severe mucositis was the dose limiting toxicity; it occurred in three of six patients treated at a dose of 1.6 mg/m2/d. The MTD was defined as 1.4 mg/m2/day by the phase I design. Upon expansion of the number of patients, 3 of 10 patients had grade 4 mucositis and 1 of 10 patients had grade 3 diarrhea. Nausea and vomiting were uncommon. No complete or partial remission was observed in 37 evaluable patients. However, 9-AC/CD exhibited antileukemic activity, as reflected by the finding of marrow hypoplasia on day 14 in 46% of the patients. Average steady-state concentration of 9-AC lactone was close to 10 nmol/l, and the of 9-AC lactone area under curve (AUC) was 1409 +/- 705 nmol/l. hr. CONCLUSION: The MTD of 9-AC/CD given as a seven-day continuous infusion was 1.4 mg/m2/d (9.8 mg/m2/course) in patients with acute leukemia. This represents three to fourfold dose escalation compared with the MTD of 9-AC given as shorter continuous infusion (three days) in patients with solid tumors. Future studies will determine the activity of prolonged administration of 9-AC/CD in patients with better prognosis acute leukemia.
Adult↗
Treatment of chronic myelogenous leukemia with interleukin-2: a phase II study in 21 patients.
We designed a phase II study to assess the activity of recombinant interleukin-2 (rIL-2) in patients with chronic myelogenous leukemia (CML). Study population included 11 patients in the chronic phase of CML (6 in hematologic remission and 5 with active disease), 6 patients in the accelerated phase, and 4 in blastic phase of CML. Patients received three 5-day cycles administrated every other week. rIL-2 was given as intravenous bolus infusions of 8 x 10(6) IU/m2 three times a day during cycle 1 and twice a day during cycles 2 and 3. Response to rIL-2 was assessed on day 45. No hematologic response was achieved in the patients with evaluable disease. One patient in hematologic remission with rIL-2 achieved a major response (from 72% to 9% Ph+ metaphases), and two patients had some degree of reduction of Ph+ metaphases. Responses were short-lived (< 6 months), but two of these three patients achieved a new cytogenetic response with interferon given post-rIL-2. A significant immune activation was achieved with rIL-2 including a marked increase in CD3+/CD25+ cells, CD56+ cells, and in natural killer/lymphokine activated killer cell cytotoxic activity. These results confirm preclinical studies, which showed that IL-2 has antileukemic activity in CML. However, the responses observed were short lived and restricted to a subgroup of patients with low disease burden. This invites further studies testing its impact in situations of minimal disease or in combination with other cytokines.
Adolescent↗
Topotecan and cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia.
PURPOSE: To evaluate the efficacy and safety of the combination of topotecan and cytarabine in patients with myelodysplastic syndromes (MDSs) and chronic myelomonocytic leukemia (CMML). PATIENTS AND METHODS: Fifty-nine patients with MDSs and 27 with CMML were enrolled. They were either previously untreated (66%) or had received only biologic agents (14%) or chemotherapy with or without biologic agents (20%). Treatment consisted of topotecan 1.25 mg/m(2) by continuous intravenous infusion daily for 5 days and cytarabine 1. 0 g/m(2) by infusion over 2 hours daily for 5 days. Prophylaxis included antibacterial, antifungal, and antiviral agents. At a median follow-up of 7 months, all 86 patients were assessable for response and toxicity. RESULTS: Complete remission (CR) was observed in 48 patients (56%; 61% with MDSs, 44% with CMML; P =.15). Similar CR rates were observed for patients with good-risk and poor-risk MDS (70% and 56%, respectively). The treatment effectively induced CR in patients with a poor-prognosis karyotype involving chromosomes 5 and 7 (CR, 71%) and secondary MDSs (CR, 72%). Fifty-four patients received one induction course, 25 patients received two, and the rest received more than two. The median number of continuation courses was two. The median overall duration of CR was 34 weeks (50 weeks for MDSs and 33 weeks for CMML). The median survival was 60 weeks for MDS and 44 weeks for CMML patients. CR and survival durations were longer in patients with refractory anemia with excess blasts (RAEB). Grade 3 or 4 mucositis or diarrhea was observed in three patients each. Fever was observed in 63%, and infections in 49% of patients. Six patients (7%) died during induction therapy. CONCLUSION: Topotecan and cytarabine induced high CR rates in unselected patients with MDSs and CMML, particularly among patients with poor-prognosis cytogenetics and secondary MDSs. Topotecan-cytarabine is an active induction regimen in MDS and CMML patients, is well tolerated, and is associated with a low mortality rate.
Adult↗
Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution.
High dose chemotherapy with autologous stem cell transplantation (ASCT) is increasingly used in the treatment of patients with lymphoma. As previously shown with conventional treatments, second neoplasms are emerging as a long term complication of the procedure. In this study, we investigate the incidence of second neoplasm in a cohort of 171 patients treated with BEAM or BEAC regimens for Hodgkin's disease (n = 62) and non-Hodgkin's lymphomas (n = 109) followed up for a median of 52 months post ASCT. Six patients developed six second malignancies 12 to 105 months after ASCT: fibrolamellar carcinoma of the liver, malignant fibrous histiocytoma, pancreatic carcinoma, squamous cell carcinoma of the lung, invasive carcinoma of the vulva and acute myelogenous leukemia. The cumulative actuarial risk for developing second malignancy is 16.7% (95% confidence interval: 5.9-39.3%) 13 years after transplant. The age-adjusted incidence of cancer in the study group is 4.1 times higher than that of primary cancer in the general population. These data confirm that ASCT recipients are at increased risk of later malignancies. This complication adds significant morbidity and mortality to the transplant process and therefore, needs to be taken into account in long term evaluation of new strategies which involve early intensification in the treatment of lymphomas.
Adolescent↗