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Background The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). Methods Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/[m.sup.2], paclitaxel at 175 mg/[m.sup.2], and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. Results Median relative dose intensity in the High-ICE arm was 293% (range = 174%-392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% CI = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% CI = 67% to 87%] and n = 48 [68%, 95% CI = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High-ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade [greater than or equal to] 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High-ICE treatment was predictably associated with severe myelosuppression, and five patients (8%) died from toxicity. Conclusions The long-term outcome of SCLC was not improved by raising the dose intensity of ICE chemotherapy by threefold.

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2–10%), the 1 year overall survival rate was 62% (95% CI: 53–70%) with a median overall survival of 16.8 months (95% CI: 12.9–21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.

Cisplatin is the drug of choice in the treatment of non-small cell lung cancer. This drug was used in combination with mitomycin and vindesine in the treatment of 205 patients with non-small cell lung cancer; a total of 183 patients could be evaluated and were used to determine which factors correlate best with improved survival. An overall response rate of 41 percent was achieved, consistent with other studies of cisplatin. However, only six patients achieved a complete response. The estimated overall average survival period of the patients was 239 days. Multivariate statistical analysis revealed patients with disease that had spread to additional organs had a poorer response and prognosis. Also, a patient history which included prior treatment with radiation conferred a higher risk of poor response and disease progression. A total of eight treatment centers contributed to this study, and patient prognosis was greatly affected by the center at which the treatment took place. No explanation is available for this observation, which was statistically highly significant. Both the quality of delivering and evaluating the effects of chemotherapy must be carefully examined before this variation may be satisfactorily explained. Although the therapy under study produced many partial responses, it must be primarily considered a treatment that only relieves symptoms, and has considerable side effects, including bone marrow suppression and nausea. Sixteen percent of the patients in the present study refused to continue with chemotherapy due to the side effects. (Consumer Summary produced by Reliance Medical Information, Inc.)

The purpose of this review was to summarize available data on uveal melanoma biology and treatment in order to provide the medical community with a basic reference that would help to make further progress in this rare disease, which remains difficult to treat.

Epithelioid neoplasms are generally carcinomas. As confirmation that every rule is meant to be broken, some sarcomas demonstrate epithelioid morphology, and can even express cytokeratins. These sarcomas have unique behavior, for example, a much higher rate of lymph node metastasis than other sarcomas. This group of sarcomas also presents diagnostic and therapeutic challenges to those clinicians who help patients contend with these difficult tumors. In this review, some of the major categories of epithelioid soft tissue tumors are described, with clinical data reported as available. Some of these tumors provide excellent opportunities to examine newer protein-targeted agents in investigational settings.

Acquired genomic aberrations have been shown to significantly impact survival in several hematologic malignancies. We analyzed the prognostic value of the most frequent chromosomal changes in a large series of patients with newly diagnosed symptomatic myeloma prospectively enrolled in homogeneous therapeutic trials. All the 1064 patients enrolled in the IFM99 trials conducted by the Intergroupe Francophone du Myélome benefited from an interphase fluorescence in situ hybridization analysis performed on purified bone marrow plasma cells. They were systematically screened for the following genomic aberrations: del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p). Chromosomal changes were observed in 90% of the patients. The del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p) were present in 48%, 21%, 14%, 39%, 13%, and 11% of the patients, respectively. After a median follow-up of 41 months, univariate statistical analyses revealed that del(13), t(4;14), nonhyperdiploidy, and del(17p) negatively impacted both the event-free survival and the overall survival, whereas t(11;14) and MYC translocations did not influence the prognosis. Multivariate analyses on 513 patients annotated for all the parameters showed that only t(4;14) and del(17p) retained prognostic value for both the event-free and overall survivals. When compared with the currently used International Staging System, this prognostic model compares favorably. In myeloma, the genomic aberrations t(4;14) and del(17p), together with β2-microglobulin level, are important independent predictors of survival. These findings have implications for the design of risk-adapted treatment strategies.

Newer chemotherapeutic protocols as well as high-dose chemotherapy have increased the response rate in myeloma. However, these treatments are not curative. Effective maintenance strategies are now required to prolong the duration of response. We conducted a randomized trial of maintenance treatment with thalidomide and pamidronate. Two months after high-dose therapy, 597 patients younger than age 65 years were randomly assigned to receive no maintenance (arm A), pamidronate (arm B), or pamidronate plus thalidomide (arm C). A complete or very good partial response was achieved by 55% of patients in arm A, 57% in arm B, and 67% in arm C (P= .03). The 3-year postrandomization probability of event-free survival was 36% in arm A, 37% in arm B, and 52% in arm C (P< .009). The 4-year postdiagnosis probability of survival was 77% in arm A, 74% in arm B, and 87% in arm C (P< .04). The proportion of patients who had skeletal events was 24% in arm A, 21% in arm B, and 18% in arm C (P= .4). Thalidomide is an effective maintenance therapy in patients with multiple myeloma. Maintenance treatment with pamidronate does not decrease the incidence of bone events.

Adding temozolomide (TMZ) to standard radiotherapy as a first‐line therapy for glioma may increase costs to a disproportionate degree compared with the resulting survival benefits.Forty‐six consecutive patients (28 males and 18 females; median age, 52 years; age range, 24–70 years) received concomitant TMZ with radiotherapy for 6 weeks followed by adjuvant TMZ for 6 cycles, and they were followed until disease recurrence and then until death. The authors assessed the costs associated with the four phases of treatment from a hospital‐centered perspective.Treatment was discontinued early in 3 patients, 9 patients, and 15 patients during concomitant TMZ, before adjuvant TMZ, and during adjuvant TMZ, respectively. Karnofsky index values varied between 85% (at the beginning of treatment) and 76% (at the end of treatment). The nature of care after disease recurrence was diverse. Overall survival ranged from 1.4 months to 64.3 months (median, 15.8 months) and was better if surgical debulking could be carried out before treatment. Global costs amounted to &euro;39,092 ± &euro;21,948 (concomitant TMZ, &euro;14,539 ± &euro;4998; adjuvant TMZ, &euro;13,651 ± &euro;4320; follow‐up, &euro;6363 ± &euro;6917; and recurrence, &euro;12,344 ± &euro;18,327), with 53% of these costs being related to the acquisition of TMZ; this represented an eightfold increase in cost compared with radiotherapy alone.TMZ may be an effective but costly adjuvant outpatient therapy for patients with glioblastoma multiforme. Definite cost‐effectiveness/utility must be assessed in a randomized Phase III trial. Cancer 2004. © 2004 American Cancer Society.

Hematopoietic stem cells (HSCs), with their dual ability for self-renewal and multilineage differentiation, constitute an essential component of hematopoietic transplantations. Human fetal liver (FL) represents a promising alternative HSC source, and we previously reported simple culture conditions allowing long-term expansion of FL hematopoietic progenitors. In the present study, we used the nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenotransplantation assay to confirm that human FL is rich in NOD/SCID-repopulating cells (SRCs) and to show that these culture conditions repeatedly maintained short- and long-term SRCs from various FL samples for at least 28 days. Quantitative limited dilution analysis in NOD/SCID mice demonstrated for the first time that a 10- to over a 100-fold net expansion of FL SRCs could be achieved after 28 days of culture. The efficiency of this culture system may lead to an increase in the use of FL as a source of HSCs for transplantation in adult patients, as previously demonstrated with umbilical cord blood under different culture conditions. (Blood. 2004;103:1166-1170)

After antigenic challenge, naive T lymphocytes enter a program of proliferation and differentiation during the course of which they acquire effector functions and may ultimately become memory cells. In humans, the pathways of effector and memory T-cell differentiation remain poorly defined. Here we describe the properties of 2 CD8+ T-lymphocyte subsets, RA+CCR7–27+28+ and RA+CCR7–27+28–, in human peripheral blood. These cells display phenotypic and functional features that are intermediate between naive and effector T cells. Like naive T lymphocytes, both subsets show relatively long telomeres. However, unlike the naive population, these T cells exhibit reduced levels of T-cell receptor excision circles (TRECs), indicating they have undergone additional rounds of in vivo cell division. Furthermore, we show that they also share effector-type properties. At equivalent in vivo replicative history, the 2 subsets express high levels of Fas/CD95 and CD11a, as well as increasing levels of effector mediators such as granzyme B, perforin, interferon γ, and tumor necrosis factor α. Both display partial ex vivo cytolytic activity and can be found among cytomegalovirus-specific cytolytic T cells. Taken together, our data point to the presence of T cells with intermediate effector-like functions and suggest that these subsets consist of T lymphocytes that are evolving toward a more differentiated effector or effector-memory stage.

After antigenic challenge, naive T lymphocytes enter a program of proliferation and differentiation during the course of which they acquire effector functions and may ultimately become memory cells. In humans, the pathways of effector and memory T-cell differentiation remain poorly defined. Here we describe the properties of 2 CD8+T-lymphocyte subsets, RA+CCR7–27+28+and RA+CCR7–27+28–, in human peripheral blood. These cells display phenotypic and functional features that are intermediate between naive and effector T cells. Like naive T lymphocytes, both subsets show relatively long telomeres. However, unlike the naive population, these T cells exhibit reduced levels of T-cell receptor excision circles (TRECs), indicating they have undergone additional rounds of in vivo cell division. Furthermore, we show that they also share effector-type properties. At equivalent in vivo replicative history, the 2 subsets express high levels of Fas/CD95 and CD11a, as well as increasing levels of effector mediators such as granzyme B, perforin, interferon γ, and tumor necrosis factor α. Both display partial ex vivo cytolytic activity and can be found among cytomegalovirus-specific cytolytic T cells. Taken together, our data point to the presence of T cells with intermediate effector-like functions and suggest that these subsets consist of T lymphocytes that are evolving toward a more differentiated effector or effector-memory stage.

Bcl-2 and bcl-xL function as suppressors of programmed cell death. The expression of bcl-2 protein in vivo is associated with long-lived hematopoietic cells such as mature lymphocytes and early myeloid progenitors. Bcl-xL, a homologue of bcl-2, is also expressed in lymphocytes and thymocytes. In contrast, the bcl-2-related proteins (bax, bad, and bak) act by promoting apoptotic cell death as shown from their expression in hematopoietic cell lines. We analyzed the expression of bcl-2 and bcl-x proteins in hematopoietic precursors obtained from various cell sources in adult mobilized peripheral blood collected from 13 patients with solid tumors, 8 adult bone marrow, and 12 umbilical cord blood. The analysis was based on the expression of the proliferation and activation specific antigens, CD38 and class II (HLA-DR). Similarly, we analyzed the expression of bcl-2-related proteins bcl-xL, bax, bad, and bak before and during ex-vivo expansion. Hematopoietic precursors expressing strongly the CD34 antigen (CD34s+) and lacking CD38 or HLA-DR expression were analyzed by using three-color immunofluorescence staining. The majority of CD34+ cells expressed bcl-2 and unexpectedly showed a bimodal distribution of low and high expression. More cells that lacked or expressed low density CD38 expressed low bcl-2 than the more differentiated counterparts (those with high density CD38). Immaturity (ie, little or no HLA-DR) is associated with the expression of low bcl-2 compared with HLA-DR+. However, HLA-DR-/low population contained a lower number of cells expressing low bcl-2 (30% to 40%) than CD38-/low in comparable samples. The hematopoietic precursors with bcl-2low and bcl-2high formed a homogeneous population of undifferentiated lymphoid-like cells having a similar forward scatter. These cells expressed strongly the bcl-xL protein (>95%) but were bax low (4% to 12%), bad low (0% to 0.8%), and bak low (0% to 3%). The expression of apoptosis specific protein (ASP) was also low (3.4% ± 3.1%) as was Annexin V. In addition, the CD34+/CD38-showed low cell cycle activity (<2.2%). Induction of apoptosis by overnight incubation of CD34 cells in serum-deprived medium resulted in the upregulation of bcl-2 as a single population histogram. Thus, these results suggest that in quiescent hematopoietic precursors, the bcl-2 protein plays a less prominent role as a survival promoter than bcl-xL and that the low bcl-2 expression did not promote apoptosis. During day 10 of ex vivo expansion of CD34+cells in liquid culture containing stem cell factor, interleukin-3 (IL-3), IL-6, IL-1ß, and erythropoietin, the CD34+/CD38- cells expressed high bcl-2 as a single population histogram, and greater than 90% were bcl-xL high. However, the expression of pro- and apoptotic antigens increased: bax (10% to 15%), bad (5% to 8%), bak (6% to 14%), and ASP (6% to 10%). These results show the importance of monitoring the expression of these proteins when defining the culture conditions for ex vivo expansion. © 1998 by The American Society of Hematology.

Abstract: Purpose: Depletion of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT) has been shown to increase tumor sensitivity to chloroethylnitrosoureas. Temozolomide (TMZ), an analogue of dacarbazine, can deplete AT, suggesting that it may be used to sensitize tumors to chloroethylnitrosoureas. However, the influence of nitrosoureas on the pharmacokinetics of TMZ is unknown, and a pilot study was performed to assess the pharmacokinetics of TMZ given via, various routes to 29 patients (27 malignant melanomas, 2 gliomas) with or without sequential administration of i.v. fotemustine. Methods: On day 1, TMZ was given intravenously (i.v.), orally (p.o.), or by intrahepatic arterial infusion (h.i.a.) at four ascending dose levels (150 to 350 mg/m2 per day). On day 2 the same dose of TMZ was given by the same route (or by another route in six patients for determination of its bioavailability), followed 4 h later by fotemustine infusion at 100 mg/m2. Plasma and urinary levels of TMZ were determined on days 1 and 2 by high-performance liquid chromatography after solid-phase extraction. Results: The pharmacokinetics of i.v. TMZ appeared linear, with the area under the curve (AUC) increasing in proportion to the dose expressed in milligrams per square meter (r = 0.86 and 0.91 for days 1 and 2, respectively). The clearance after i.v. administration was 220 ± 48 and 241 ± 39 ml/min on days 1 and 2, respectively. The apparent clearance after p.o. and h.i.a. administration was 290 ± 86 and 344 ± 77 ml/min, respectively. The volume of distribution of TMZ after i.v., p.o., and h.i.a. administration was 0.4, 0.6, and 0.6 l/kg on day 1 and 0.5, 0.5, and 0.6 l/kg on day 2, respectively. The absolute bioavailability of TMZ was 0.96 ± 0.1, regardless of the sequence of the i.v.-p.o. or p.o.-i.v. administration, confirming that TMZ is not subject to a marked first-pass effect. A comparison of TMZ pharmacokinetics after i.v. and h.i.a. treatment at the same infusion rate revealed little evidence of hepatic extraction of TMZ. However, the systemic exposure to TMZ (AUC) appeared to decrease at a lower infusion rate. TMZ excreted unchanged in the urine accounted for 5.9 ± 3.4% of the dose, with low within-patient and high interpatient variability. TMZ crosses the blood-brain barrier and the concentration detected in CSF amounted to 9%, 28%, and 29% of the corresponding plasma levels (three patients). The equilibrium between plasma and ascitic fluid was reached after 2 h (assessed in one patient). Conclusion: The sequential administration of fotemustine at 4 h after TMZ treatment had no clinically relevant influence on the pharmacokinetics of TMZ. The potential clinical effect of TMZ given by h.i.a. or by locoregional administration has yet to be established, as has the impact of the infusion duration on patients' tolerance and response rate.

No relevant conflicts of interest to declare.

The IFM99-03 and IFM99-04 trials were conducted from April 2000 to August 2004. Patients younger than 66 years with high-risk (b2microglobulin > 3 and chromosome 13 deletion by FISH analysis at diagnosis) de novo multiple myeloma (MM) were included and prospectively treated. In both protocols, induction regimen consisted of VAD (4 courses) followed by melphalan 200 mg/m2 (HDM200) plus autologous peripheral blood stem cell transplantation (ASCT). When a HLA-sibling donor was available, ASCT was followed by reduced-intensity conditioning regimen (RIC) allograft (fludarabine, antithymocyte globulin and low dose busulfan): IFM9903 protocol (Garban et al, Blood2006;107:3474–3480). When no donor was available, patients were randomised to receive a second ASCT with HDM220 +/− anti-IL6 monoclonal antibody (BE-8, 250 mg total dose, Diaclone Besançon, France): IFM99-04 protocol (Moreau et al, Blood2006;107:397–403).284 patients met eligibility criteria and received at least one course of VAD. 65 had an available HLA-identical sibling donor and were included in the IFM99-03 trial, and 219 were included in the IFM 99-04 trial. Patients were older in the tandem ASCT trial (median age, 58 vs 54 years; P = .006) and the b2-microglobulin level was also higher in the latter group (median, 4.9 mg/L vs 4.1 mg/L; P = .049). At the reference date of July 1st, 2008, on an intent-to-treat basis, considering the entire population of 284 patients, with a median follow-up of 56 months, the EFS did not significantly differ from tandem ASCT to single autograft followed by allo-RIC (median 22 vs 19 months, P = 0.58). Nevertheless, there was a trend for a superior OS in the double ASCT trial (median 48 vs 34 months, P = 0.07). When considering the comparison of the results of the 166 patients /219 who completed the whole tandem ASCT protocol with those of the 46 patients /65 who underwent the entire auto/allo-RIC program, no difference was observed regarding EFS (median 25 vs 21 months, P = 0.88), but there was again a trend for a superior OS in favour of double ASCT (median OS, 57 vs 41 months, P = 0.08), due to a longer survival after relapse in the tandem ASCT arm. These long-term results indicate that, in a subgroup of high-risk patients with de novo MM, a tandem autologous transplant procedure is at least equivalent or even superior to a combination of autologous followed by RIC allogeneic stem cell transplantation.

High dose therapy (HDT) supported with autologous stem cell transplantation has been introduced in the management of myeloma. However, after a single or a double transplantation, almost all patients ultimately relapse. New strategies are required to control the residual disease after HDT. The “Intergroupe Françophone du Myélome” (IFM) initiated a trial designed to evaluate the impact of maintenance treatment with Thalidomide on the duration of response after HDT. From April 2000 to October 2003, 1017 myeloma patients at diagnosis under the age of 65 years were enrolled in the IFM 99 protocol. 780 of them, without or with only one adverse prognostic factor (beta-2 microglobuline ≥ 3 mg/l or deletion of chromosome 13), were enrolled in the IFM 99 02 protocol. They received the following treatment: 1) 3–4 cycles of the VAD regimen; 2) a first autologous transplant prepared with Melphalan 140 mg/m2; 3) a second autologous transplant prepared with Melphalan 200 mg/m2. Patients without progressive disease 2 months after the second transplant were randomized to receive: no maintenance treatment (arm A), maintenance treatment with Pamidronate (arm B) or maintenance treatment with Thalidomide and Pamidronate (arm C). As of June 2005, 593 patients (76%) have been randomized: 197 in arm A, 195 in arm B and 201 in arm C. Clinical characteristics of each group were similar. The median follow-up from diagnosis was 3 years (1 to 6 y). Thalidomide was found to improve the Event-free-survival (EFS). Indeed, the 4-year post-diagnosis probability of EFS was 39% (95% CI= 29–51) in arm A, 37% (95% CI= 26–48) in arm B, and 50% (95% CI= 37–60) in arm C (p<0.02). We compared EFS according to the treatment groups in different subgroups of patients (beta-2-microglobulin ≤ 2.5 mg/l, beta-2-microglobulin > 2.5 mg/l, deletion of chromosome 13, and no deletion of chromosome 13). Thalidomide was found to improve the 4-year EFS of patients without deletion of chromosome 13 (39% in arm A, 38% in arm B, 52% in arm C, p<0.01) and of patients with a beta-2-microglobulin > 2.5 mg/l at diagnosis (28% in arm A, 21% in arm B, 57% in arm C, p<0.001). On the opposite, patients with a deletion of chromosome 13 or with a beta-2-microglobulin ≤ 2.5 mg/l at diagnosis did not benefit significantly from Thalidomide (p=0.5 and p=0.9, respectively). The 4-year overall survival was similar in the 3 treatment groups: 86% in arm A, 78% in arm B, and 86% in arm C (NS). Among the 593 randomized patients, 3 factors were found to be associated with a longer EFS in the multivariate analysis: low beta-2-microglobulin at diagnosis (p<0.03), treatment arm (p<0.02), and deletion of chromosome 13 (p<0.03). In conclusion, the final analysis of the IFM9902 trial demonstrates that Thalidomide improves the duration of response after high dose therapy among patients with myeloma, especially those who have a beta-2-microglobulin >2.5 mg/l without deletion of chromosome 13.

Infectious complications in transplanted patients (pts) motivate recommendations that autologous stem cell transplantation (ASCT) should be carried out in special rooms endowed with positive pressure and high-efficiency particulate air filtration (HEPA) filters. However growing indications for ASCT and cost restrictions prompt to lighten the procedure without compromising the safety. We report here 59 consecutive and non-selected ASCTs performed from 2/00 to 4/04 in conventional single rooms (without positive pressure air filtration) to analyze early toxicity, infectious complications and 100-days (d.) transplant related death (TRD). High-dose chemotherapy (HDC) and ASCT were administered for non-Hodgkin’s lymphoma (n=39), multiple myeloma (n=13) and Hodgkin’s lymphoma (n=2). Five pts with multiple myeloma received double ASCT. Median (med.) age was 54 years (range 22–71). Med. number (nb.) of previous lines of treatment was 1 (range 1–6). Thirty-nine pts were intensified in 1st remission (26 CR, 11 PR, 2 MR), 12 in 2nd remission (10 CR, 2 PR), 1 in 3rd CR and 2 in either SD or refractory relapse. Except for amphotericin-B mouthwashes and oral valacyclovir in case of HSV seropositivity, no systemic prophylactic antibiotic (abt) was used. The med. nb. of reinfused stem cells was 3.7x106 CD34+/kg (1.86–33.3). One pt received 0.94x106 CD34+ cells/kg combined with bone marrow. G-CSF was started at day 7 (2–15) after transplant. Med. time to achieve an absolute neutrophil count >0.5x109/L and >1.0x109/L was respectively (resp.) 10 d. (8–13) and 11 d. (8–13). Med. time to spontaneous platelet count >20x109/L and >50x109/L was resp. 11 d. (0–28) and 13 d. (9–81). The med. nb. of red cells and platelets transfusions was resp. 2 (0–12) and 2 (0–25). Except five pts, all developed fever (>38.3°C) and 56 out of the 59 pts received abt for a med. duration of 12 d. (1–46). Twenty-six pts (44%) had fever without any documented infection. Grade3/4 infections were diagnosed in 27 pts (46%). One patient presented candidemia. No case of aspergillosis was observed. Two pts (3%) needed transient transfer to the intensive care unit because of septicemia with reversible cardio-respiratory failure. The med duration of hospitalization was 20 d. (2–75), and was <28 d. for 54/59 pts (92%). With a med. follow up of 22.6 months (3–52), 44 patients are still alive: 33 (61%) in CR and 11 (20%) with relapse. 11 patients died: 8 from progressive disease, one following allotransplant 12 months after ASCT and one at d. 104 due to thrombotic thrombocytopenic purpura. The later was the unique TRD. The profile of toxicity and the low TRD rate observed in our non selected pts are comparable to whose reported usually in the literature for pts treated in sterile units with HEPA, confirming that HDC and ASCT can be safely realized in conventional single rooms.

High dose therapy (HDT) supported with autologous stem cell transplantation has been introduced in the management of aggressive myeloma. However, after single or tandem transplantation, almost all patients ultimately relapse. New strategies are required to control any residual disease after HDT. The Intergroupe Francophone du Myelome (IFM) initiated a trial designed to evaluate the impact of maintenance treatment with Thalidomide on the duration of response after HDT. From April 2000 to October 2003, 1004 myeloma patients at diagnosis under the age of 65 years were enrolled in the IFM 99 protocol. 780 of them, without or with only one adverse prognostic factor (beta-2 microglobuline >3 mg/l or deletion of chromosome 13), were enrolled in the IFM 99 02 protocol. They were to receive the following treatment: 1) 3–4 cycles of the VAD regimen; 2) a first autologous transplant prepared with Melphalan 140 mg/m2; 3) a second autologous transplant prepared with Melphalan 200 mg/m2. Patients without progressive disease 2 months after the second transplant were randomized to receive: no maintenance treatment (arm A), maintenance treatment with Pamidronate (arm B) or maintenance treatment with Thalidomide and Pamidronate (arm C). As of May 2004, 580 patients (74%) have been randomized: 195 in arm A, 190 in arm B and 195 in arm C. Clinical characteristics of each group were similar. The median follow-up from diagnosis was 26 months (range: 6–50) Thalidomide was found to improve the Progression-free survival (PFS; p<0.007) and the Event-free-survival (EFS; p<0.01). Indeed, the 40-months post-diagnosis probability of PFS was 70% (95% CI= 42–80) in the Thalidomide arm versus 53% (95% CI= 37–65) in arm A, and 52% (95% CI= 36–68) in arm B. Most patients (60%) enrolled in arm A and B received Thalidomide at time of relapse. The overall survival was similar in the 3 treatment groups. Among the 580 randomized patients, 2 factors were found to be associated with a longer EFS : low beta-2-microglobulin at diagnosis (p<0.01) and treatment arm (p<0.01). Deletion of chromosome 13 (FISH analysis) was not related to EFS. In conclusion, the first analysis of the IFM9902 trial strongly suggests that Thalidomide is an effective maintenance treatment after high dose therapy for myeloma. The next analysis (November 2004) will be presented during the meeting.