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E Archimbaud

Publications and source records attributed to E Archimbaud.

At least 19 recordsLinked to original sources
PubMed2003

Prior and concurrent administration of recombinant human megakaryocyte growth and development factor in patients receiving consolidation chemotherapy for de novo acute myeloid leukemia--a randomized, placebo-controlled, double-blind safety and efficacy study.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) administered after acute myeloid leukemia (AML) chemotherapy (CT) failed to shorten the time of transfusion-dependent thrombocytopenia in a previous study. In this multicenter, randomized, placebo-controlled, double-blind study we determined the effect of administration of PEG-rHuMGDF prior to CT and of administration prior, concurrent, and 1 day post CT on platelet recovery and transfusion requirements in patients receiving consolidation CT for de novo AML. Patients were randomized to receive either 30 microk/kg PEG-rHuMGDF as a single dose on day -6 ( n=37), placebo as a single dose on day -6 ( n=9), 30 microk/kg PEG-rHuMGDF administered on day -6 followed by 10 microg/kg on days -5 to day 6 (through CT and including the day after CT, n=35), or placebo administered on day -6 to day 6 ( n=9). The median times to transfusion-independent platelet recovery to >20x10(9)/l were 24.5 and 24.0 days in the PEG-rHuMGDF day -6 group and PEG-rHuMGDF day -6 to 6, respectively, compared to 21.0 days in the placebo group. There were no significant differences in the number of days of platelet transfusions between either PEG-rHuMGDF schedule or placebo. The PEG-rHuMGDF day -6 to 6 group had a delayed absolute neutrophil count (ANC) recovery compared to either placebo or PEG-rHuMGDF day -6 treated patients. Thus, alteration of the scheduling of PEG-rHuMGDF in terms of earlier dosing before and during chemotherapy did not improve platelet recovery but rather delayed hematopoietic reconstitution. Although unexpected, these observations may be of major relevance for the design of future clinical trials with recombinant thrombopoietins.

Adult↗
PubMed2001

Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS.

This study investigated the feasibility of allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) as postconsolidation therapy for patients with myelodysplastic syndromes (MDSs) or acute myeloid leukemia after MDS. Patients with a histocompatible sibling were candidates for alloSCT and the remaining patients for ASCT. Remission-induction therapy consisted of 1 or 2 courses with idarubicin, cytarabine, and etoposide, followed by one intensive consolidation course with cytarabine and mitoxantrone. Initially, bone marrow cells were used for ASCT. Subsequently, mobilized blood stem cells were used in an attempt to shorten posttransplantation hypoplasia. With a median follow-up of 3.6 years the 184 evaluable patients showed a 4-year survival rate of 26% and a median survival of 13 months. The remission-induction chemotherapy induced complete remission (CR) in 100 patients (54%). The 4-year disease-free survival (DFS) rate was 29% and the median DFS was 12 months. Twenty-eight of 39 patients (72%) with a donor were allografted in CR-1, including 2 patients who underwent transplantation in CR-1 without a consolidation course. Thirty-six of 59 patients (61%) without a donor received ASCT in CR-1. The 4-year DFS rates in the group of patients with or without a donor were 31% and 27%, respectively. The 4-year survival rates from CR were 36% and 33%, respectively. This large prospective study shows the feasibility of both alloSCT and ASCT. This treatment approach leads to a relatively high remission rate, and the majority of patients in remission received the SCT in CR-1. The ongoing study investigates whether this approach is better than treatment with chemotherapy only.

Adult↗
PubMed2000

[Effectiveness of combined vancomycin and pefloxacine in gastrointestinal decontamination for preventing infections after chemotherapy-induced bone marrow aplasia. A randomized double-blind study].

OBJECTIVE: To test the value of the combination of pefloxacin and vancomycin as gastro-intestinal tract decontamination for the prevention of infections in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: Oral pefloxacin plus vancomycin (48 patients), pefloxacin alone (51 patients), or placebo (52 patients) were administered in a randomized double-blind study. Evaluation was done by determining site and documentation of infections, organisms responsible for bacteriologically documented infections, organisms acquired in surveillance cultures and number of days with fever during aplasia. RESULTS: Patients receiving pefloxacin had significantly fewer episodes of bacteremia with enterobacteriacae. No differences were noted between patients treated by pefloxacin and those who received a combination of pefloxacin with vancomycin regarding gram-positive (Gram+) infections and infections with gram-negative (Gram-) organisms usually resistant to pefloxacin. However, placebo gave similar results. There was no induction of resistance to pefloxacin during the study. Tolerance of treatment was excellent. Only a prolonged aplasia has been observed in patients receiving pefloxacin. CONCLUSION: Thus, the combination of vancomycin with pefloxacin was not more efficacious than pefloxacin only for the prevention of Gram+ infections in the neutropenic patient. The systematic use of antibiotics as gastrointestinal tract decontamination for the prevention of infections in patients with aplasia may be questionable.

Adult↗
PubMed2000

Impact of pre-induction therapy leukapheresis on treatment outcome in adult acute myelogenous leukemia presenting with hyperleukocytosis.

Acute myeloid leukemia (AML) presenting with hyperleukocytosis is generally of poor prognosis due to an increased early death rate and a lower response to initial chemotherapy. Between April 1985 and December 1995, all patients with newly diagnosed AML admitted to our institution with an initial white blood cell (WBC) count greater than 100 x 10(9)/l were scheduled to undergo leukapheresis. This represented 53 patients (median age 59 years, range 16-78 years) who underwent from 1 to 4 sets of leukapheresis (median 1). The median initial WBC count was 160 x 10(9)/l (range 100-480 x 10(9)/l). Morphologic subtypes, according to the French-American-British classification, showed 3 M0, 16 M1, 6 M2, 10 M4, 16 M5, and 2 unclassified cases of AML. In 21 patients (40%), leukapheresis did not reduce their WBC counts significantly, while 32 patients (60%) achieved a WBC count of less than 100 x 10(9)/l (median 71 x 10(9)/l) after leukapheresis. Analysis of cell cycle was performed on bone marrow (BM) and peripheral blood leukemic cells before and after leukapheresis in three cases. In two of those cases, a recruitment of BM leukemic cells in the S phase was observed after leukapheresis. The median WBC count at the time of starting chemotherapy was 85 x 10(9)/l (range 23-264 x 10(9)/l). Complete remission was achieved in 55% (95% confidence interval 40-68%). Early death occurred in two cases. Median disease-free survival was 10 months, while median overall survival was 8 months. In this study, early death rate is lower than data previously published in the literature and almost all patients could receive chemotherapy. This might suggest a benefit of initial leukapheresis in the treatment of AML presenting with hyperleukocytosis.

Adolescent↗
PubMed2000

Dose-escalation study of single dose mitoxantrone in combination with timed sequential chemotherapy in patients with refractory or relapsing acute myelogenous leukemia.

A dose-escalation study was realized in order to assess the maximally tolerated dose (MTD) of high-dose mitoxantrone in a single injection combined with cytarabine and etoposide (EMA regimen) in refractory or relapsed acute myelogenous leukemia (AML). Between July 1997 and June 1998, 24 patients with relapsed or refractory AML entered the study. All but one patient had normal left ventricular ejection fraction (LVEF) at baseline. Performance status according to World Health Organization (WHO) criteria was less than two in all cases. All patients have been previously treated by mitoxantrone or anthracyclines. Four cohort of ten patients were scheduled with the following doses: (1) mitoxantrone 36 mg/m2 on day 1; (2) mitoxantrone 45 mg/m2 on day 1; (3) mitoxantrone 60 mg/m2 on day 1; (4) mitoxantrone 75 mg/m2 on day 1 in combination with cytarabine 500 mg/m2 per day (days 1-3, and days 8-10), and etoposide 200 mg/m2 per day (days 8-10). All patients received the full doses of the three drugs. The limiting toxicity was defined as WHO grade 4 nonhematologic toxicity and for impairment of cardiac function by Alexander's criteria (moderate or severe toxicity). The occurrence of limiting toxicity in at least three patients from the same dose level determined the MDT. No limiting toxicity was observed in mitoxantrone dose level 1. Two limiting toxicities were observed in mitoxantrone dose level 2 (one mucositis, one moderate cardiac toxicity), and three limiting toxicities in mitoxantrone dose level 3 (1 high transaminase levels, two moderate cardiac toxicities) ending the assay. Overall, 16 patients (67%) achieved complete remission (CR). One drug-addict patient died from cerebral hemorrhage due to severe aspergillosis and was not considered as a limiting toxicity. After EMA chemotherapy, 13 patients received subsequent chemotherapy courses involving anthracyclines or their derivatives. Six patients underwent allogeneic bone marrow transplantation. No late toxicity occurred. The median survival of the entire cohort was 41.4 weeks. We conclude that (i) EMA chemotherapy using a single injection of mitoxantrone is effective in the treatment of refractory or relapsing AML; (ii) the recommended phase II dose of mitoxantrone is 45 mg/m2 administered over 30 min as a single dose in combination with cytarabine and etoposide.

Adolescent↗
PubMed2000

Transplantation with selected autologous peripheral blood CD34+Thy1+ hematopoietic stem cells (HSCs) in multiple myeloma: impact of HSC dose on engraftment, safety, and immune reconstitution.

OBJECTIVE: The aims of our study performed in myeloma were to evaluate the performance and the safety of Systemix's high-speed clinical cell sorter, to assess the safety and efficacy of deescalating cell dose cohorts of CD34+Thyl+ hematopoietic stem cells (HSCs) as autologous grafts by determining engraftment, and to assess the residual tumor cell contamination using polymerase chain reaction (PCR) amplification assays of patient-specific complementarity determining region III (CDR III) analysis for residual myeloma cells. MATERIALS AND METHODS: The clinical trial was performed in 31 multiple myeloma patients, using purified human CD34+Thyl+ HSCs mobilized from peripheral blood with cyclosphosphamide and granulocyte-macrophage colony-stimulating factor to support a single transplant after high-dose melphalan 140 mg/m2 alone (cohort 1) and with total body irradiation (TBI) (cohorts 2-5) after an HSC transplant cell dose de-escalation/escalation design. RESULTS: Twenty-three patients were transplanted. Engraftment data in the melphalan + TBI cohorts confirmed that HSC doses above the threshold dose of 0.8 x 10(6) CD34+Thy1+ HSCs/ kg provided prompt engraftment (absolute neutrophil count >0.5 x 10(9)/L day 10; platelet count >50 x 10(9)/L day 13). A higher rate of infections was observed in the early and late follow-up phases than usually reported after CD34+ selected or unselected autologous transplantation, which did not correlate with the CD34+Thy1+ HSC dose infused. Successful PCR for CDR III could only be performed in five patients on initial apheresis product and final CD34+Thy1+ HSC product and showed a median tumor log reduction >3.12. CONCLUSIONS: CD34+Thy1+ HSCs are markedly depleted or free of detectable tumor cells in multiple myeloma and are capable of producing fast and durable hematopoietic reconstitution at cell doses >0.8 x 10(6) CD34+Thy1+ HSCs/kg. The delayed immune reconstitution observed is not different from that described in unselected autologous bone marrow and peripheral blood mononucleated cells transplants in multiple myeloma and may be corrected by addition of T cells either to the graft or to the patient in the posttransplant phase.

Adult↗
PubMed2000

Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Française de Greffe de Moelle (SFGM).

To assess the place of allogeneic hematopoietic stem cell transplantation (HSCT) in the advanced stage of acute myeloid leukemia (AML), we retrospectively analyzed 379 consecutive patients who underwent allogeneic HSCT for advanced AML. The median follow-up of the entire cohort was 7.5 years. Sixty-nine patients (18%) were transplanted with primary resistant disease. Three hundred and ten (82%) were relapsed patients, 94 (30%) of whom were in untreated relapse, 67 (22%) in refractory relapse and 149 (48%) in 2nd or 3rd complete remission at time of transplantation. The 5-year probabilities of overall survival (OS), disease-free survival (DFS), and transplant-related mortality (TRM) were 22 +/- 4%, 20 +/- 4%, 45 +/- 6%, respectively. In multivariate analysis, we demonstrated the favorable impact on OS, DFS and TRM of two factors over which we have no control (age <15 years, complete remission achievement) and three factors over which we have some control (female donor, acute and chronic graft-versus-host disease). The results of this study suggest that the graft-versus-leukemia effect is important in advanced AML and that new HSCT modalities are needed for some patients with this indication.

Acute Disease↗
PubMed2000

Itraconazole lung concentrations in haematological patients.

Itraconazole distribution is largely dependent on its high liposolubility. Intrapulmonary lung concentrations remain unknown in haematological patients. We report itraconazole lung concentrations in such patients treated with itraconazole. Itraconazole and hydroxyitraconazole were measured by high-performance liquid chromatography in concomitant blood samples and lung post-mortem biopsies (three cases) or lung lobectomy (one case). These itraconazole and metabolite lung concentrations were sufficient to be active on Aspergillus.

Adult↗
PubMed1999

A randomized, double-blind, placebo-controlled study with pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) as an adjunct to chemotherapy for adults with de novo acute myeloid leukemia.

To determine the safety, biologic, and clinical benefits of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF; Amgen, Thousand Oaks, CA) after myelosuppressive chemotherapy in acute myeloid leukemia (AML), 108 adult patients with de novo AML were randomized to receive either PEG-rHuMGDF (2.5 microg/kg/d or 5 microg/kg/d) for up to 21 doses (group A), a single dose of 2.5 microg/kg PEG-rHuMGDF, 7 daily doses of 2.5 microg/kg PEG-rHuMGDF (group B), or placebo. The greatest biologic activity was seen in group A with a median peak platelet count of 1,084 x 10(9)/L, occurring at a median 9 days after the last dose of study drug, compared with 517 x 10(9)/L and 390 x 10(9)/L in group B and placebo group, respectively. Thrombocytosis (platelets >1,000 x 10(9)/L) was seen at rates of 52%, 8%, and 9% in groups A, B, and placebo, respectively, but were not associated with any adverse event. There was no effect on median time to transfusion independent platelet recovery (> or = 20 x 10(9)/L). The median time to neutrophil recovery (> or = 500/microL) and red blood cell transfusion requirements were similar in all groups, and there was no apparent stimulation of leukemia. PEG-rHuMGDF was biologically active and well tolerated. Further investigation of dose and scheduling is required, specifically earlier dosing before and during chemotherapy.

Acute Disease↗
PubMed1999

A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group.

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA-->CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients </=75 years of age and with newly diagnosed APL were included. Induction treatment was stratified on white blood cell (WBC) count and age: patients </=65 years of age and with an initial WBC count of </=5,000/microL (n = 208) were randomized between ATRA-->CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/microL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA -->CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P =.0002) and close to significance in the elderly group (P =.086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA-->CT group (P =.04, relative risk [RR] =.41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA-->CT group (P =.1, RR =.62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P =.0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P =.02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had relapsed. Overall survival was improved in patients who received maintenance CT (P =.01), and there was a trend for better survival in patients who received maintenance ATRA (P =.22). Our findings strongly suggest that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA can reduce the incidence of relapse in APL. This effect already translates into significantly better survival for maintenance treatment with continuous CT.

Adolescent↗
PubMed1999

Hypermethylation of calcitonin gene in adult acute leukemia at diagnosis and during complete remission.

Hypermethylation of the calcitonin gene has been described in various hematologic malignancies. In order to assess its frequency and potential usefulness as a marker for leukemic cells and to detect potential clinical correlations, 180 adult patients (aged > 15 years) with newly diagnosed acute leukemia including 133 cases of acute myeloid leukemia (AML) and 47 cases of acute lymphoblastic leukemia (ALL) were tested for its presence in leukemic blasts at diagnosis by Southern blot technique and polymerase chain reaction (PCR) using 3 sets of primers (P550, P566, P1400), amplifying the most frequent sites of hypermethylation upstream or within the gene. In AML, 92 patients (69%) had hypermethylation detected by Southern blot at diagnosis. This hypermethylation could be confirmed by PCR in 18 of 36 tested cases (50%). Hypermethylation was not significantly associated to any clinical or hematological characteristic of the disease. In ALL, 44 patients (94%) had hypermethylation detected by Southern blot at diagnosis. This hypermethylation could be confirmed by PCR in 33 of the 43 tested cases (77%). Sensitivity of PCR assessed by dilution was 1 to 0.1%. Hypermethylation was not either significantly related to any clinical or hematologic characteristics of the disease. Seven ALL cases which were positive by PCR at diagnosis and achieved cytological CR could be tested during CR. Five cases were negative and did not relapse after 3 to 27 months in CR. One case was positive at the beginning of CR and became negative after autologous transplant. However, he relapsed after 9 months in CR, 3 months after the last negative test. PCR for Bcr/Abl was also negative at this time. We conclude that hypermethylation of the calcitonine gene is frequent at diagnosis in adult acute leukemia, particularly in ALL.

Acute Disease↗
PubMed1999

Impact of cyclosporine and methylprednisolone dose used for prophylaxis and therapy of graft-versus-host disease on survival and relapse after allogeneic bone marrow transplantation.

In order to determine whether doses of cyclosporine and methylprednisolone used for prophylaxis and therapy of acute graft-versus-host disease (GVHD) have any influence on relapse and survival following allogeneic bone marrow transplantation (BMT), we studied 176 adult patients with hematologic malignancies, who underwent a first allogeneic transplant from an HLA-identical sibling donor. Two methods of management of acute GVHD used in two different centers were compared: group I included 62 patients who had 'standard' management of GVHD including prophylaxis with 1-3 mg/kg/day of cyclosporine and treatment with 2 mg/kg/day of methylprednisolone when acute GVHD developed; group II included 114 patients who received 'intensive' management of GVHD including prophylaxis with 5 mg/kg/day of cyclosporine and treatment with high-dose methylprednisolone (8-20 mg/kg/day for 3 days) at the onset of GVHD. The overall incidence of GVHD was the same in both groups. However, acute GVHD was more severe in group I than in group II (P < 0.0001), with consequently less resolution of GVHD after treatment in group I (61%) than in group II (80%) (P = 0.06). Overall survival and disease-free survival (DFS) did not differ between the two groups. However, actuarial risk of disease relapse was significantly higher in group II than in group I (36% vs 17%, P = 0.02). In a multivariate analysis taking into account known factors influencing GVHD and relapse, only type of GVHD management and age were significantly predictive for the occurrence of GVHD, while only type of GVHD management and pathology other than chronic myeloid leukemia (CML) were predictive for relapse. This study demonstrates that intensity of GVHD prophylaxis and therapy can influence the graft-versus-leukemia effect by decreasing severity of GVHD but at the price of increasing relapse rate post transplant.

Acute Disease↗
PubMed1999

Multicenter randomized phase II trial of idarubicin vs mitoxantrone, combined with VP-16 and cytarabine for induction/consolidation therapy, followed by a feasibility study of autologous peripheral blood stem cell transplantation in elderly patients with acute myeloid leukemia.

To compare the antileukemic efficacy of idarubicin and mitoxantrone in elderly patients with acute myeloid leukemia (AML) and to evaluate the feasibility of autologous transplantation using PBSC after consolidation in those with a good performance status, 160 patients (median age 69 years), with AML at diagnosis, 118 of them with de novo AML and 42 with AML secondary to myelodysplastic syndrome or toxic exposure (sAML), received induction treatment with idarubicin, 8 mg/m2/day or mitoxantrone, 7 mg/m2/day, on days 1, 3, and 5, both combined with VP-16, 100 mg/m2/day on days 1 to 3 and cytarabine (araC), 100 mg/m2/day, on days 1 to 7. G-CSF, 5 microg/kg/day, was administered after chemotherapy in patients aged more than 70 years. Patients in complete remission (CR) received one course of consolidation using the same schedule as for induction except the araC administration was shortened to 5 days. Some patients younger than 70 years were then scheduled for autologous stem cell harvest on days 5 to 7 of G-CSF, 5 microg/kg/day, initiated after hematopoietic recovery from consolidation. Autologous transplantation was performed following an additional chemotherapy conditioning. Ninety-five patients (59%) achieved CR, without significant difference between the idarubicin (56% CR) and mitoxantrone (63% CR) group. There was also no significant difference in CR rate between de novo AML (63%) and secondary AML (55%) (P = 0.12). Patients aged < 70 years had 67% CR, while patients aged > or = 70 years had 49% (P = 0.02). There was no significant difference in the duration of aplasia between the two arms. Median time to neutrophil recovery was 22 days in patients who received G-CSF following induction and 27 days in patients who did not (P = 0.006). Severe extrahematologic toxicities of induction did not differ between the two arms and included sepsis (39%), diarrhea (13%), hyperbilirubinemia (8%), hemorrhage (6%) and vomiting (6%). Overall, 14 patients (9%), died from toxicity of induction. First consolidation was administered in 74 patients of whom seven (9%) died from toxicity. Nineteen patients have received transplantation. Median time to recovery of neutrophils > 0.5 x 10(9)/l was 13 days and of platelets > 50 x 10(9)/l 43 days following consolidation. There were two toxic deaths. Median disease-free survival and survival from time of achieving CR of non transplanted patients are 6 and 7 months respectively without difference between the two arms. Fourteen transplanted patients relapsed at a median of 5 months post-transplant. We conclude that this regimen is well tolerated and has a good efficacy to induce CR, without a significant difference in efficacy and toxicity between idarubicin and mitoxantrone. Intensive postinduction, including transplantation, is feasible; however, this procedure did not seem to prevent early relapse in the majority of patients. Neither the high rate of CR nor consolidation nor transplant procedure in a selected group of patients did translate into improved DFS and/or survival.

Acute Disease↗
PubMed1999

Granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase efficacy of intensive sequential chemotherapy with etoposide, mitoxantrone and cytarabine (EMA) in previously treated acute myeloid leukemia: a multicenter randomized placebo-controlled trial (EMA91 Trial).

The EMA86 study showed efficacy of intensive sequential chemotherapy with mitoxantrone, 12 mg/m2 day on days 1-3, etoposide, 200 mg/m2/day as a continuous infusion on days 8-10 and cytarabine (araC), 500 mg/m2/day as continuous infusion on days 1-3 and 8-10 (EMA regimen) in previously treated patients with AML. The goal of the EMA91 study was to determine whether administration of GM-CSF between the two sequences of EMA chemotherapy and during the second sequence could increase therapeutic efficacy by potentially increasing leukemic cell recruitment into the S phase of cell cycle before the second sequence. One hundred and ninety-two patients aged less than 65 years with previously treated AML received GM-CSF, 5 microg/kg/day or placebo from day 4 to day 8 of EMA chemotherapy. One hundred and twenty were refractory and 72 were in first relapse after a complete remission (CR) of more than 6 months duration. CR rates after one course of chemotherapy were 65% in the GM-CSF group (refractory: 51%; first relapse: 89%), not significantly different from the 59% CR rate (refractory: 46%; first relapse: 81%) in the placebo group. Median time to recovery of neutrophils was 38 and 37 days and median time to last platelet transfusion 32 and 32 days respectively in the GM-CSF and placebo groups. WHO grade > or = 3 non-hematologic toxicities were mainly sepsis (45% and 51%, respectively) and mucositis (34% and 31%) and did not differ between the two groups. Toxic death rate was 5% and 8%, respectively, in the GM-CSF and placebo groups. Patients achieving CR were scheduled to receive six courses of maintenance with reduced-dose EMA. Time to progression tended to be longer in the GM-CSF group (median 154 vs 115 days, progression-free rate at 18 months 33% vs 19%, P = 0.08), particularly in refractory patients (P = 0.06). However, at the current follow-up, this did not translate into a significantly longer disease-free survival and survival. Cell cycle studies showed increased recruitment of cells in the S phase between day 4 and day 8 in the GM-CSF group compared to placebo (P = 0.006). However, this did not significantly relate to prognosis in this cohort of patients. GM-CSF might marginally increase efficacy of sequential chemotherapy without increasing its toxicity in the absence of any detected relationship between this effect and observed leukemic cell recruitment into the cell cycle.

Acute Disease↗
PubMed1999

Continuous-infusion carboplatin in combination with idarubicin or mitoxantrone for high-risk acute myeloid leukemia: a randomised phase II study.

Fifty-three patients of median age 66 years (39 patients > 60 yrs), including 5 with FAB unclassified or secondary acute myeloid leukemia (AML) at diagnosis, 14 with resistant AML, 19 in first and 15 in subsequent relapse, were treated with carboplatin (CBP), 200 mg/m2/day, as a continuous infusion, (days 3 to 7) with mitoxantrone (MIT) or idarubicin (IDA), (12 mg/m2/day) as an i.v. bolus, on days 1 to 3. Results were evaluated after one induction course. Overall, 15 patients (28% [95% confidence interval (CI), 17-42%], 8/28 with IDA and 7/25 with MIT) achieved complete remission (CR). There was no statistical difference between IDA and MIT arms. Fourty-nine percent (95% CI, 35-63%) had resistant disease (53% IDA versus 44% MIT respectively) and 23% (95% CI, 12-36%) died from toxicity (18% IDA versus 28% MIT). Median durations of neutrophils less than 0.5 x 10(9)/l and platelet counts less than 20 x 10(9)/l were 32 and 32 days respectively in the IDA arm and 31 and 26 days respectively in the MIT arm. Severe toxicity included infections (45%), diarrhea (21%), bleeding (9%), vomiting (7%), hyperbilirubinemia (6%), mucositis (4%) (no statistical difference was seen between both arms). Nephrotoxicity was observed in only one case in the IDA arm. Cardiac toxicity included reversible pulmonary oedema in one patient in the IDA arm. No severe ototoxicity was noted. CR patients received maintenance courses with 3 days of CBP and one day of IDA or MIT. Median survival was 2 months (range, 1-30+ months) and 2.5 months (range, 0.5-19.5 months), and median disease-free survival (DFS) 2 months (range, 1-30+ months) and 2.5 months (range, 1-14 months) in the IDA and MIT arms respectively. We conclude that CBP at a cumulative dosage of 1 g/m2 together with intercalating agents (IDA/MIT) has antileukemic efficacy in elderly patients.

Adult↗
PubMed1998

Expression of beta1-integrins and pseudo-immunoglobulins on acute promyelocytic leukemia cells and its modifications during in vitro differentiation.

Adhesion molecules are involved in cell-cell interactions and therefore probably play a role in the differentiation and egress of cells from the bone marrow, which might be potentially important in the biology of acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) is known to induce in vitro and in vivo differentiation of APL cells and to favor their release from the bone marrow into the blood at initiation of therapy. In order to determine whether these effects might be mediated in part by modifications of beta1-integrin and pseudoimmunoglobulin expression on APL cells, the expression of these adhesion molecules on bone marrow (BM) blast cells from 24 APL patients was assayed at diagnosis by an indirect immunofluorescence method. CD49b, CD49d, CD49e, CD49f, CD54, CD58, and CD56 were expressed respectively on 18%+/-20% (0-66%), 40%+/-31% (0-96%), 48%+/-32% (0-97%), 29%+29% (1-94%), 51%+/-30% (5-98%), 37%+/-24% (1-85%) and 32%+/-31% (0-97%) of APL cells, with respectively 39%, 71%, 79%, 50%, 70%, 70%, and 53% positive cases (> or = 20% positive cells). Despite a wide variability between individual samples, the expression of beta1-integrins and that of pseudo-immunoglobulins tended to be higher in APL in comparison with that of a cohort of 63 patients with other AML subtypes with significant differences for CD54 expression (51%+/-30% vs 28%+/-27%, P=0.006) and CD56 expression (37%+/-24% vs 17%+/-19%, P=0.0003). An in vitro differentiation assay was performed in nine cases. Cells were harvested after 4-7 days of culture and studied for the expression of adhesion molecules. Granulocytic differentiation was marked by persistence of CD15 expression. Antigen expression was decreased after culture with ATRA for all beta1-integrins (except CD49b and CD49f) and pseudoimmunoglobulins (except CD54) tested. However, changes were statistically significant only for CD56 (P=0.04), CD49d (P=0.02) and CD49e (P=0.01). The modifications in the expression of the beta1-integrins and pseudo immunoglobulins were not specific to ATRA-induced differentiation, but commonly observed with differentiation. Furthermore, the modifications in the adhesive properties of APL cells to extracellular matrix proteins, observed on adhesion assays, were not statistically significant after ATRA-induced differentiation. Overall, the level of expression of beta1-integrins and pseudo-immunoglobulins was higher in APL than in other AML subtypes, and appeared modified with induced differentiation. This was not specific of ATRA, but might be involved in the general differentiation phenomenon. The modulation of adhesion molecules does not seem a sufficient requisite for the development of the retinoic acid syndrome, but could nevertheless be part of the increase in leukocyte counts observed during the first days of ATRA therapy.

Adolescent↗
PubMed1998

Differential adhesiveness between blood and marrow leukemic cells having similar pattern of VLA adhesion molecule expression.

Functional adhesion of blood and marrow leukemic cells from 14 acute myeloid leukemia patients presenting with hyperleukocytosis was evaluated by performing cytoadhesion assays on purified (extracellular matrix proteins) and non-purified supports (MRC5 fibroblastic cell line). Results, in 30-min chromium release assay, show a mean +/- S.D. adhesion to fibronectin, collagen, and laminin respectively of 30 +/- 17%, 20 +/- 13%, 25 +/- 17% for blood leukemic cells and 18 +/- 11%, 11 +/- 10%, 11 +/- 8% for marrow leukemic cells. These differences between blood and marrow cells were statistically significant (respectively P = 0.005, P = 0.01 and P = 0.002), while no difference was noted regarding adhesion to non-purified supports. The higher adhesion of blood blast cells to purified supports was observed regardless of CD34 expression. No significant difference was observed in the expression of cell surface VLA-molecules (CD29, CD49b, CD49d, CD49e, CD49f) between blood and marrow blast cells. The addition of GM-CSF or G-CSF induced increased adhesion of marrow blasts and decreased adhesion of blood blasts leading to a loss of the difference between blood and marrow cells. In a 60-min chromium release assay, marrow blasts adhered even more than blood leukemic cells to fibronectin. In contrast, marrow blasts from 'aleukemic' acute myeloid leukemia patients did not show any modification regarding their adhesion to extracellular matrix proteins when co-cultured with growth factors.

Antigens, CD↗
PubMed1998

Thrombopoietic factors potentially useful in the treatment of acute leukemia.

Thrombocytopenia is a major cause of morbidity following intensive chemotherapy for acute leukemia. Over recent years, there has been an increasing use of platelet transfusions which, although generally efficacious to prevent severe hemorrhage, have associated risks of transmitting blood-borne disease and of alloimmunization. Therefore, there is a clinical requirement for a drug that will reliably alleviate the thrombocytopenia associated with leukemia therapy. The c-mpl ligand thrombopoietin is the most interesting factor for the treatment of thrombocytopenia because of its lineage specificity. Phase I and II studies confirm its biological efficacy to induce rise in platelet count in patients with solid tumors and acute leukemia. Several other pleiotropic hematopoietic growth factors are also currently in clinical trials. These include interleukin-6, interleukin-3, interleukin-11, PIXY321 and stem cell factor. The effects of these cytokines appear to be modest at most and, with the exception of interleukin-11, their side effects are likely to limit their clinical application. Combinations of factors may prove more efficacious approaches to enhance platelet recovery.

Acute Disease↗