Abstract 3225
Poster Board III-162
Autologous Stem Cell Transplantation (ASCT) with Peripheral Blood Stem Cells (PBSC) is widely used in first line treatment for Multiple Myeloma (MM) patients. The ...rapidity and stability of cell engraftment may correlate with the number of CD34+ cells in the autograft. However, the impact of this number on hematologic recovery and long term outcomes is not very well defined yet. Having a higher number of collected CD34+ cells seems to be a very important and accessible objective in 2009 (availability of mobilization agents), also it has in the same time cost and efficacy results.
This study concerned 130 MM patients who underwent ASCT in our center between years 2000 and 2007. There were 79 males and 51 females with a median age of 56.8 years (34-72). At diagnosis there were 71 IgG (49κ, 22λ 26 IgA (15κ,11λ 2 IgD (1κ, 1λ 27 light chain (18κ,9λ 2 plasma cell leukemia and 2 nonsecretory. According to the IMWG classification, there were 11 patients in stage I (10A and 1B), 12 IIA, 96 III(75A and 21B) and 11 not classified. At diagnosis, 24 patients had a del(13), and 65 had high levels of β2microglobulin. The median interval between diagnosis and ASCT was 7.8 months (3.5-131). Before transplantation, all patients received granulocyte-colony stimulating factor (G-CSF) 5μg/kg/day, PBSC were mobilized in steady state in 135 cases, 62 after G-CSF + cyclophosphamide. As conditioning, all pts received melphalan alone with a median total dose of 304mg (130-440). Sixty six patients received a single ASCT and 64 patients received 2 ASCT in a double ASCT program. After transplantation, there were 2 graft failure, 40% of patients received red blood cell (RBC) transfusions (median number: 0 0-23), and 64% received platelet transfusions (median number: 1 0-20). The median number of days with neutrophils <0.5G/L was 6 (0-33) and with platelets <20G/L was 17 (2-104). The median length of hospitalization for auto transplantation was 18 days (14-54). To assess the impact of the infused CD34+ cells number, we have analyzed 2 groups: group 1 (n=86) for ASCT with a number of CD34+ ≤3×106/kg and group 2 (n=107) for ASCT with a number of CD34+ >3×106/kg.
We found a high significant impact of the high number of infused CD34+(group 2) on platelets recovery (p=0.002). The univariate analysis using Cox model, showed a trend for the high number of infused CD34+ cells (group2) on leukocyte recovery O.R= 0.748 0.5-1.0 (p=0.0568) and a high significant impact of the same group on neutrophils recovery O.R= 0.670 0.5-0.9 (p=0.009). These results were not changed even after adjustment on age also on the sequential number of the ASCT in the double auto ASCT program. The multivariate analysis using Cox model, studying the impact of CD34+ group, age, gender, poor prognostic factors high level of β2microglobulin and del(13), mobilization (G-CSF alone or G-CSF + cyclophsphamide), showed a significant impact only of poor prognostic factors on overall survival O.R.= 7.94 1.0-59.2 (p=0.04) and also on progression free survival (PFS) O.R.= 2.55 1.1-5.7 (p=0.024).
High level of infused CD34+ appeared to be very optimal for hematological recovery after ATSC in MM, without any significant impact on O.S and PFS. An economical study is running on this population to assess the impact of this level on hospitalization and treatment costs, results will communicated in the future.
No relevant conflicts of interest to declare.
Abstract One hundred and fifty-four acute myeloid leukemia patients with trisomy 8 were studied for their clinical and biological characteristics, and treatment outcome. Forty-seven patients ...presented with trisomy 8 as the sole aberration, 107 with trisomy 8 associated with other cytogenetic abnormalities (13 with favorable, 54 with intermediate, and 40 with unfavorable risk cytogenetics). Overall complete remission (CR) proportion was 48%. Median disease-free survival (DFS) and overall survival (OS) were 7.8 and 8.3 months, respectively. In multivariate analysis, age ≥60 years ( P < 0.0001) and association with unfavorable karyotype ( P = 0.03) were of poor prognostic value for CR achievement. Age ≥60 years ( P < 0.0001) and antecedents of dysmyelopoiesis ( P = 0.02) were of poor prognostic value for OS. Patients with trisomy 8 alone did not show any difference in terms of outcome as compared with those in whom trisomy 8 was associated to intermediate risk cytogenetics ( P = 0.0002). Trisomy 8 in addition to favorable karyotype maintained a good clinical outcome, while trisomy 8 in addition to unfavorable cytogenetics showed the worst prognosis.
Abstract Background The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of response and overall survival. Identification of valuable factors that ...can facilitate therapeutic decision-making between intensive chemotherapy and investigational treatment strategies is warranted. Methods Analysis of proliferative (white blood cell WBC count) and invasive (percentage of blast cells in peripheral blood) characteristics of leukemic blasts at diagnosis is presented in a population of 432 promyelocytic leukemia AML patients who are older than than 60 years and have been selected for entering onto five successive clinical trials combining an anthracycline and cytarabine. Results Five groups of patients were defined according to these two relevant parameters used in clinical practice. Response rates were lower for the hyperproliferative groups (47% and 46%, respectively) and the nonproliferative groups displaying circulating blasts (56% and 59%, respectively) compared with those for the nonproliferative and noninvasive group (77%) ( P = .0003). Median overall survivals were shorter for the hyperproliferative groups (5.7 and 5.8 months, respectively) compared with those observed for the nonproliferative groups (8.9 and12.6 months, respectively). Conclusions This combination of basic characteristics helps estimate the outcome of elderly AML patients who are usually selected for intensive chemotherapy. Although these factors remain valuable for identifying leukemia behavior, our study demonstrated that results of intensive chemotherapy in elderly patients remained poor, whatever the prognostic group. Comparison with recent data from the literature requires investigators to study results differently and to consider investigational therapy as being the most appropriate treatment even for this highly selected population.
Abstract 4124
We reported our experience on the antifungal prophylaxis by posaconazole in patients with acute myeloblastic leukaemia (AML) who were exposed to induction chemotherapy. To validate the ...benefit of an antifungal prophylaxis in this kind of population, we conducted a prospective study giving posaconazole (200mg per os x 3/24h) to all AML patients hospitalized for induction in the period 2007-2008 (group I) and to compare the observed results (incidence of severe invasive aspergillosis and overall survival) with a control group (group II) which was represented by all AML patients hospitalized for induction during the period 2006-2007 and who did not received any antifungal prophylaxis. There was in total 143 AML patients and after matching on age, gender, FAB classification and molecular markers, we got 121 patients (59 males and 62 females with a median age of 55 years): 55 patients in group I and 66 patients in group II. There were 91 AML de novo and 30 secondary AML, 18 patients had good cytogenetic markers, 43 intermediate and 58 poor (2 non evaluated). According to cytogenetics plus molecular markers, we distinguished 2 groups: a good prognostic group (n=29) associating favourable cytogenetics and intermediate 1 (normal cytogenetics+ Flt3 ITD, CEBPA,NMP1) and a poor prognosis group (n=75) with unfavourable cytogenetics and intermediate 2 (17 patients were not determined). As induction chemotherapy, patients received different combinations according to protocols, age and AML characteristics. The median interval between AML diagnosis and hospitalization was 0 day (-41 – +7), 92 patients (76%) were placed in laminar air flow rooms. After induction, 100 patients achieved a CR and 2 patients died during induction period. The median duration of aplasia and of hospitalization were 28 days (7 – 91) and 37 days (22 – 101) respectively. There was no significant difference for all the above characteristics between group I and group II. Concerning posaconazole prophylaxis, the treatment was started the 1st day of chemotherapy with a median duration of 27 days (8-94): 35 patients (64%) received their prophylaxis until their discharge, 7 (13%) discontinued due to toxicity hepatic (n=3), renal (n=1), transfer to intensive care unit (n=3) and 13 (23%) switched to another fungal treatment because of IA suspicion (n=5), probable IA (n=2) and invasive candidosis (n=5).
At Day32 post induction, we observed 2 probable IA (3.6%) in group I and 8 IA possible (n=4) + probable IA (n=4) (12%) in group II (p = 0.085). The cumulative incidence of IA in group I and II was: at day 100, 7.27% vs 15.5%, at 1 year 12.72% vs 22.72% and at 18 months 14.54% vs 24.24% respectively. The Kaplan-Myer analysis on time to death from any cause at Day 100, showed a significant survival benefit in favour of the Pozaconazole group (group I) over the control group (group II) (p=0.0023) (figure1), this difference was also significant when we adjusted the analysis only on deaths caused by IA (figure2). After a median follow-up of 8.6 months, the probability of overall survival was 92.3% at day 100, 83.5% at 6 months, 70% at 1 year, 58% at 18 months and 36% at 2 years with a significant difference between groups I and II(p=0.02). At the last follow-up, 39 patients died in the group II and 10 in the group I. Concerning the other risk factors, the multivariate analysis showed a significant impact on long term OS of age HR= 0.103 (0.02 – 0.5) (p= 0.00029) , cytogenetics HR=2.524 (1.172-5.44) (p=0.0018) and response to induction HR=7.73 (3.579-16.7) (p=1.9e-7).
We showed a very important impact of anti-fungal prophylaxis in patients undergoing chemotherapy for AML especially for invasive aspergillosis, which is a risk factor to take into account in addition to age, cytogenetics and response to treatment.
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No relevant conflicts of interest to declare.
Abstract 1010
Poster Board I-32
Invasive aspergillosis remains an important cause of death for AML patients. Recently a lot of efficient innovative agents have been proposed as curative, empiric and ...more recently prophylaxis therapy in the IFI setting. It has been demonstrated that some agents used either as early treatment or prophylaxis of IFI had a significant impact on early survival (Day 100) of AML patients. The principal aim of our study was to see if this observation was true when considering a long-term period and how the development of an IA during the AML story interferes on the therapeutic strategy and finally on the long-term survival. We decided to conduct a study in our centre from 2004 to 2009 on a cohort of AML patients and to compare patients who developed an IA with patients who never developed in IA during the period of observation. Chi2 test and Fischer exact test were used for the comparison of discrete variables, U Mann-Withney test for continuous variables, survival analysis used Kaplan-Meyer and Cox proportional hazard model. We studied a total of 267 patients which represented 151 716 patient-days at risk (415 patient-years) and the longer follow-up was 5.1 years. Sixty-three patients developed an IA: 7 (11%) proven, 24 (38%) probable and 32 (51%) possible. The median delay between chemotherapy induction and IA was 22 days (IQR 16-29). The characteristics of the population were 123 females and 144 males (54%) with a median age of 56.7 years (47.9-64.9). The performance status (PS) 0 (n=94/35%), 1 (n=102/38%), 2 (n=50/19%), 3 (n=13/5%), 4 (n=8/3%), FAB classification 0 (n=17/6%), 1 (n=45/17%), 2 (n=42/16%), 3 (n=20/8%), 4 (n=28/10%), 5 (n=68/26%), 6 (n=8/3%), 7 (n=14/5%) (25 patients were not classified) and the cytogenetics were favourable (n=26/10%), intermediate (n=98/38%) and unfavourable (n=111/42%) (26 patients were not classified). As induction treatment patients received standard chemotherapy (n=180/67%), intensive regimen (n=86/32%) and 1 patient (1%) received low dose chemotherapy. At the last follow-up 115 patients have relapsed (43%), 100 are alive and 167 died. All characteristics below were compared between patients with and without IA during their disease course and 4 variables were significantly different (Table 1).The probability of overall survival was at the end of induction (D 30): 95% (86-98) with IA and 98% (95-99) without IA, at day 100: 79% (67-87) with IA and 92% (88-96) without IA, at 1 year 49% (36-60) with IA and 66% (60-73) without IA, at 2 years 33% (21-46) with IA and 43% (37-51) without IA and at 4 years 15% (5-30) with IA and 32% (24-40) without IA(Figure 1). The median survival time was 1.51 years (95%CI 1.19-1.88) with 1 year (95%CI 0.60-1.89) with IA and 1.62 years (95%CI 1.33-2.18) without IA. The univariate analysis on OS showed a significant influence of IA (p=0.028), age (p<0.001), cytogenetics (p<0.001), chemotherapy (better survival for intensive therapy compared to standard p<0.001) and a trend for period of diagnosis (better survival in ≥2007 vs before 2007: p=0.08). The multivariate analysis showed a significant impact on OS of IA, age, PS and cytogenetics (Table 2).In conclusion, IA appears as a significant risk factor besides age, PS, cytogenetics either on short or on long-term survival in AML. Differences of IA incidence observed over time may be related to prophylaxis strategy (environment, antifungal prophylaxis) applied during different periods. These results point out the importance of antifungal prophylaxis for fit AML patients
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No relevant conflicts of interest to declare.
This analysis studied 197 autologous HSCT performed in 132 patients treated for multiple myeloma (MM) in our center between 2000 and 2007. There were 53 females and 79 males with a median age of 56.8 ...years (34–72). At diagnosis there were 71 IgG (49κ, 22λ), 26 IgA (15κ,11λ), 2 IgD (1κ, 1λ), 27 light chain (18κ,9λ), 2 plasma cell leukemia, 3 non secretory, 1 non secretory/non excretory. There were 11 stage I (10A and 1B), 12 IIA, 96 III(75A and 21B) and 13 not classified. At diagnosis, 24/98pts had a del(13), and 65/179 had high levels of β2microglobulin. Before 2004, 50% of transplants were done and the median interval between diagnosis and HSCT was 7.8 months (3.5–131). We divided the population into 2 groups (I = 65: double-auto, II = 67 simple auto). The disease status pre-transplant according to the number of apheresis were: 1 apheresis (group I: 3CR, 29PR, 3SD, 1PD; group II: 2CR, 24PR, 3PD), 2 apheresis (group I: 16PR, 1SD, 1PD; group II: 3CR, 9PR, 1PD), 3 apheresis (group I: 1CR, 4PR; group II: 10PR, 1unknown), 4 apheresis (group I: 4PR, 1PD; group II: 1CR, 10PR, 2SD), 6 apheresis (group II: 1PR) and 8 apheresis (group: 1PR). PBSC were mobilized in steady state in 135 cases, 53 after cyclophosphamide alone, 9 cyclophosphamide with other drugs. During mobilization, we used GCSF in 179cases, GM-CSF in 5cases, SCF in 4 cases and associations of GM-CSF+ GCSF in 2(1%) cases and SCF+GCSF in 7(3.5%) cases. The median number of infused cells were: TNC 5×107/kg (1–59), CFU-GM 70.5×104/kg (0–2616) and CD34+cells 3×106/kg (0–27). Of these, 115 (58%) had a number of CD34+cells<4×106/kg and 82 (42%) ≥4×106/kg. As conditioning regimens, all pts received melphalan alone with a median total dose of 304mg 130–440. After transplantation, 156(79%) have received growth factors 1(0.5%) GM-CSF, 148 (95%) G-CSF and 7 (4.5%) SCF and 195 pts well engrafted (99%). Concerning red blood cell (RBC) transfusions, 60% of pts did not received any RBC transfusions, 30% received between 1 and 4 transfusions, 7% between 5 and 8 and 3% 10 or more and concerning platelet (Pt) transfusions, 35,5% did not received any Pt transfusions, 53% received between 1 and 3, 9% between 4 and 7 and 2.5% 10 or more. The median number of RBC and Pt transfusions were 0 0–23 and 1 0–20 respectively. The median number of days with neutrophils <0.5G/L was 6 (0–33) and with Pt<50G/L 17 (2–104) and the median length of hospitalization for auto transplantation was 18 days (14–54). The probability of 5-year overall and event-free survival (OS and EFS) were 64.3% (56.3–73.4%) and 32.4% (24.9–42.2%) and the median OS was not reached. Among all pts, 25 received an allogeneic HSCT as further treatment. Statistical analysis studied age disease status at transplant infused TNC, CD34+cell and CFU-GM, growth factors during mobilization and after transplantation, mobilization chemotherapy, interval Diag-T and transplantation period in
a conditional logistic-regression model to analyze associations between these variables and length of hospitalization, number of RBC and Pt transfusions;a multivariate analysis using Cox model to analyze the impact of these variables on length of aplasia (<0.5G/L neutrophils and <50G/L Pt).
We observed no significant impact of all studied variables on length of hospitalization and RBC transfusions and a significant negative impact of long interval diagnosis-T (p=0.05) and of the period > 2004 on Pt transfusion number (p=0.03). We showed a significant positive impact of CFU-GM number HR=1 (1000–1.002) (p=0.03) and growth factor use after transplantation HR=0.55 (0.36–0.85) (p=0.005) on days <0.5 G/L neutrophils and a significant negative impact of CD34+cell<4 ×106/kg on the number of days <50G/L Pt (HR=1.65 (1.09–2.50) (p=0.01). A more refined analysis of the groups, as well as a medico-economic analysis are ongoing and will be presented. In conclusion, this retrospective analysis showed an interesting long-term overall survival probability for this high risk MM population. We demonstrated no apparent impact of the pre-transplant, mobilization, and graft variables on number of transfusions and the length of hospitalization in this global analysis. However, we did show a significant influence of the diagnosis-T interval on platelet transfusions and of the CD34+ cell number, GCSF post-transplant and CFU-GM number on the length of aplasia.
We performed a retrospective analysis from our transplant registry on first allogeneic hematopoietic stem cell transplantations (HSCT) for acute myeloid leukemia (AML) patients (pts) between 1996 and ...2007. Our principal objective was to analyze the impact of molecular markers on the long-term overall and disease-free survival (OS and DFS) after first allogeneic HSCT. We found 364 pts, only 63 pts had retrospectively available conserved cells at diagnosis. The expression levels of WT1, Evi1, Flt3 and Hoxa9 were performed by quantitative RT-RQPCR. The mutational status of MLL duplication, FLT3 (internal tandem duplication or nucleotide substitutions) (ITD), NPM1 and CEBPα were determined by PCR, RFLP and/or sequencing analysis. All pts except 1 had a karyotype analysis at diagnosis. Among these 63 pts, there were 27 (43%) males and 36 (57%) females, with a median age of 41 years (18-64). The FAB classification was M0: 6, M1: 10, M2: 13, M4: 6, M5: 21, M6: 3, M7: 1 and 3 unclassified. Concerning the karyotype analysis, 25 (40%) pts had a normal karyotype, 37 (60%) pts presented cytogenetic abnormalities classified as favourable prognosis in 5 cases (8%), intermediate in 13 cases (21%) and poor in 19 cases (31%). Regarding the molecular markers evaluated in all pts: 4(6%) pts had Flt3over-expressed (ov-ex), 19 (30%) FLT3 ITD+, 3 (5%) MLLdup, 10 (16%) Hoxa9 ov-ex, 7 (11%) Evi1 ov-ex, 15 (24%) NPM1mut+, 25 (40%) WT1 ov-ex and 1 CEBPαmut+ (this marker was evaluated only in 12 pts). Associations between these markers and the karyotype prognosis groups are shown in Figure1. Twenty three (36%) pts had no abnormal molecular markers and 40 (54%) pts had at least one abnormal marker: 10 (16%) 1 marker, 10 (16%) 2 markers, 12 (19%) 3 markers, 4 (6%) 4 markers and 4 (6%) 5 markers. Concerning the karyotype, among the 23 negative molecular pts, 22 have been evaluated and there were 9 (41%) normal, 11 (50%) poor and 2 (9%) favourable; and among the 40 positive pts, 16 (40%) were normal, 8 (20%) poor, 13 (32.5%) intermediate and 3 (7.5%) favourable. Concerning transplantation, 50% of HSCT were done after 2004 and the median interval between diagnosis and transplantation was 6 months (2.6–68.5). Before conditioning, 41 pts were in CR (26 CR1, 14 CR2 and 1 CR3), 8 in PR and 14 in relapse. Twenty five (40%) pts received a non-myelo-ablative conditioning and 38 (60%) a myelo-ablative one. There were 34 sex-mismatched (21 M→F and 13 F→M), 21 ABO incompatibility (6 minor and 15 major), 55 were HLA matched and 8 mismatched. Twenty three (36.5%) pts received PBSC, 37 (59%) bone marrow and 4 (6.5%) cord blood cells from 47 (75%) HLA siblings and 16 (25%) unrelated donors. After transplantation, 59 (94%) pts engrafted, 42 developed AGVHD (21gr1, 13 gr2 and 8 gr4), and among 51 evaluable pts, 13 developed cGVHD (7 limited and 6 extensive). At the last follow-up, 20 pts have relapsed, 29 pts are alive (28 CR and 1PR) and 34 died 18 (53%) from TRM and 16 (47%) from relapse. At the median follow-up of 48 months, the OS and DFS for the whole population were 40% (33–47) and 40% (34–46) respectively with a maximum follow-up of 130 months and for the different subgroups according to karyotype and molecular markers the results are shown in Table 1. The univariate analysis showed a significant impact of FLT3 ITD and over-expression of FLT3RQ on long-term DFS, (p=0.03 and p=0.02 respectively), and a trend on long-term OS (p=0.08). Concerning the karyotype and some other markers (MLL, EVI1, NPM1 and Hoxa9), we did not observe any significant difference because of small number of pts in some subgroups. The known benefic impact of NPM1mut+, was erased because the majority of this group presented an associated FLT3 ITD+. In addition, we are performing a multivariate analysis that will be presented. In conclusion, allogeneic HSCT in this high risk population of AML pts, allowed a good probability of long-term OS and DFS, despite the presence of high number of bad molecular markers and cytogenetic abnormalities. Finally, AML pts with FLT3 ITD+ seem not benefit from allogeneic HSCT as well as patients with NPM1mut+ associated with FLT3ITD+.
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Table 1. OS and DFS according to different molecular markers and karyotype subgroups
We conducted a retrospective single institution analysis to evaluate the immediate and long-term efficacy, tolerance, survival and time to progression of MM patients (pts) who received VELCADE (Vel.) ...as induction and in those who relapsed or were refractory after standard therapies. A total of 92 pts were included, 62 (67%) males and 30 (33%) females. Median age at treatment was 60 years 35–79. At diagnosis, there were 48 (52%) IgG, 24 (26%) IgA, 2 (2%) IgD, 15 (16%) light chains and 3 (4%) plasma cell leukaemias, 11pts (12%) were in stage I A, 12 (13%) stage IIA and 69 (75%) stage III (51 A and 18B). The median level of β2 microglobulin was 3.28 mg/l (1.12–24). Among 42 evaluated del(13), 19 (45%) were + in which there was two t(4;14)+. We defined 3 groups: group1:16 (17%) pts who received Vel. as induction, group2:58 (63%) pts who received Vel. as 2nd line n=41 or 3rd line n=17, group 3:18 (12%) pts who received Vel. as ≥ 4th line. Prior to Vel.(groups 2 and 3), 53 (70%) pts had received an autologous hematopoietic stem cell transplantation (HSCT), 13 (14%) allogeneic HSCT and 35 (46%) thalidomide (Thal.) (median dose of 200mg/day, median duration of 4 months). The median interval between diagnosis and Vel. initiation was 28.3 months (0.2–125); 28 pts had an interval less than 12 months (16 in 1st line), 27 pts between 12 and 36 months and 37 pts with more than 36 months. The median number of Vel. cycles in group 1, 2 and 3 were 42–9, 52–12 and 53–12 respectively with a standard dose of 1.3 mg/m2 decreased to 1.0 mg/m2 in case of toxicity (<3 cycles: n=18, 4–6: n=52; 7–8: n=14; >8: n=8). Fifty-two (57%) pts received an association of dexamethasone (40mg/day). There were 6 Vel. discontinuation (<3 Vel.cycles) and 25 (27%) dose reduction due to neuropathy 3cycles n=2 (17%), 4–6 cycles n=12 (23%), 7–8 cycles, n=7 (50%) and ≥9 n=4 (50%). Peripheral neuropathy occurred in 61 pts (66%) 32 (52%)gr1, 18 (30%)gr2, 9 (15%)gr3 and 4 (3%)gr4, in which, 25 (41%) had previously received Thal. 12 (48%)gr1, 8 (32%)gr2, 5 (20%)gr3. The most other common toxicities were, fatigue n=35 (38%), constipation n=18(20%), diarrhea n= 11(12%), nausea n=14(15%) and vomiting n=7(8%). The overall response rate was observed in 67 (73%) pts 13 (14%)CR, 22 (24%)VGPR and 32 (35%)PR. With a median follow-up of 23.4 months, the median overall survival (OS) for the whole population and for group 1 and 2 was not reached, and was 17 months for group 3. The probability of OS at 3 years for the whole population was 61%50–73.5 (Figure 1) and were: 80%62–100, 66%54–81 and 45%25–82.5 for groups 1, 2 and 3 respectively (Figure 2). The probability of OS at 5 years for the whole population from MM diagnosis was 72.5%63–84. The median time to progression (TTP) was 25.5 months for the whole population; it was not reached for group 1, were 25.5 and 13 months for group 2 and 3 respectively. The probability of progression-free survival (PFS) at 2 years was 51%40–64,5 for the whole population and 66%45–96, 52%39–70 and 29%12–71 for group 1, 2 and 3 respectively. We showed no significant difference in term of OS (p=0,166) and PFS (p=0.495) between the patients with del(13) 51% (31–83) and 42(23–78) and without del(13) 83%(68,5–99,6) and 58%(40–85,5). Finally we observed a better PFS at 2 years for pts receiving lenalidomide after Vel. versus those who did not, 64%42–96 and 48%36–63 respectively. The multivariate analysis (studying: age, sex, stage, beta2M, del(13), previous lines, allogeneic HSCT, Thal., and interval diag-Vel.) showed only a significant impact of thalidomide HR=3.06 (1.37–6.85) (p=0,006), and a trend for interval diag-Vel. In conclusion, this analysis showed a very good percentage of long-term OS with a median not reached for Vel. naïve or 2nd, 3rd Vel line MM pts. Moreover, we showed a significant negative impact of previous Thal. treatment and no impact of del(13).
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Following a dose-escalation study performed in order to assess the maximally tolerated dose of high-dose mitoxantrone in a single injection (45mg/m2) combined with timed-sequential chemotherapy, a ...phase II trial (EMA-2000 regimen) was performed in high-risk AML. EMA-2000 regimen was effective (complete remission: 63%), but extra-hematologic toxicity appeared very high (53% of severe infections). In order to decrease toxicity, the same regimen was proposed between February 2004 and May 2006 followed by a single administration of Pegfilgrastim.
Twenty-four patients entered the study and received mitoxantrone 45 mg/m2 on day 1 in combination with cytarabine (500 mg/m2 on days 1 to 3 and 8 to 10) and etoposide (200 mg/m2 on days 8 to 10) followed (after checking for the absence of blast in bone marrow aspirate performed at day 11) at day 12 by 6 mg of Pegfilgrastim administered by subcutaneous route. Overall, 15 patients (63%) achieved complete remission (CR) and 9 patients had resistant disease. Median time to achieve CR was 43 days. CR achievement was related to leukemia stage 50% (2/4 patients) in refractory AML and 65% (13/20 patients) in relapsed AML. Median time to granulocyte recovery > 0.5 × 109/l was 28 days. Median time to platelet recovery > 50 × 109/l was 30 days. The predominant non-hematologic toxicity remained infections with 54% of septicemia and 62% of localized infections. Other severe extra-hematologic toxicity (WHO grade > 2) were mucositis (50%), nausea and vomiting (33%), and diarrhea (17%). Pegfilgrastim was well tolerated. Nine of the 15 remitters received subsequent treatment consisting of maintenance chemotherapy courses in 3 patients, allogeneic stem cell transplantation (SCT) in 3 patients, and autologous SCT in 3 patients. Median DFS was 11.5 months with an estimated 2-year DFS rate of 37%. DFS was related to first CR duration (p = 0.01). Median OS was 12.5 months with a 2-year OS rate of 32%.
Response to therapy, toxicity and survival were compared to those of our previous EMA-2000 regimen. Patient populations were matched on age, leukemia stage, performance status, and FAB subtypes. Outcome was similar regarding CR rate and extra-hematologic toxicity. Neutrophil and platelet recovery was only 2 days and 4 days shorter with the new regimen. However median DFS and OS, and 2-year survival estimate appeared better with the new regimen (11.5 months with 37% 2-year DFS vs 7.2 months with 16%; and 12.5 months with 32% vs 8.1 months with 18% respectively). This was confirmed whatever was the result of induction therapy. In patients achieving CR, median OS was 18.4 months with 61% 1-year OS vs 9.3 months with 36%, while in patients with no CR, median OS was 9.7 months with 44% 1-year OS vs 3.7 months with 8%. These results suggest a potential differentiating or immune-regulating effect of Pelfilgrastim. None of the patients with initial hyperleukocytosis (> 10 × 109/l), who failed to achieve CR, recovered on a hyperleukocytosic mode. Biological explorations and a randomized study are warranted for confirming our results.
The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of complete responses and long-term overall survival. Therefore, a clinically usefull ...prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies in this patient population. Overall, 243 of the 432 patients (56%, 95% CI: 51–60%) achieved CR (229 of them after the first induction course and 14 after salvage therapy). The median disease-free survival (DFS) and the median overall survival (OS) of the entire cohort were 8.4 months (95% CI: 7.2–10.1 months) and 8.3 months (95% CI: 7.2–10 months) respectively. A prognostic score is presented based on the multivariate analysis of 432 newly diagnosed non-M3 AML patients aged more than 60 years, selected on the base of their initial performance status and the absence of severe co-morbidity factors, for entering onto five successive clinical trials combining an anthracycline and cytarabine. Four clinically relevant parameters are included in this index: cytogenetics at diagnosis, history of previous hematologic disorder, hematologic features at diagnosis, and LDH level at diagnosis. Using this stratification system, three risk groups were defined: a favorable-risk group A (OS of 39% at 2 years and 21% at 5 years), an intermediate-risk group B (OS of 19% at 2 years and 8% at 5 years), and a poor-risk group (OS of 5% at 2 years and 0% at 5 years). The prognostic index estimates the outcome of elderly AML patients usually selected for intensive chemotherapy trials using four easily determined parameters and might identify patients who are really candidates for this treatment strategy from those for whom investigational therapy or palliation may be most appropriate.
