Abstract 2813
Myelodysplastic syndroms (MDS) are an heterogenous diseases. In order to define prognosis of differents subgroups, several scoring are elaborated. The most used was IPSS score including ...pourcentage of blasts, number of cytopenia and cytogenetics. Recently, IPSS was revised. IPSS-R includes new cytogenetics subgroups, anemia, thrombocytopenia, neutropenia and pourcentage of blasts. These score were defined in untreated MDS and Acute Myeloid Leukemia (AML) with less 30% of blasts patients. IPSS-R score was evaluated in MDS untreated population included AML with 20–29% of blasts. Only 16% of patients were higher-risk IPSS MDS in this study (Greenberg et al., Blood 2012). Azacitidine (AZA) prolongs survival when used as first line treatment of higher-risk MDS and AML with 20–29% bone marrow (BM) blasts (Fenaux et al., Lancet Oncology 2009). The aim of this study is to evaluate efficacy of AZA in higher IPSS-R MDS and AML with 20–99% BM blasts.
We analyzed retrospectively MDS and AML patients treated by AZA in 6 centers. Patients having received ≥ 1 cycle of AZA and who had BM evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered évaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML.
The study population included 149 patients: F/M: 65/84; median age 70 (range 35–88). Median number of cycle of AZA treatment was 6 (range 1–42). Diagnosis at AZA was (RAEB-1 n=1, RAEB-2 n=69, AML n=79). Median overall survival (OS) was 11 months. For MDS population excluding AML with 20–29% of blasts, IPSS score was intermediate-1 in 16 patients, intermediate-2 in 29 patients and high in 25 patients. In using IPSS-R score, we observed IPSS-R good in 2 patients, IPSS-R intermediate in 20 patients, IPSS-R poor in 29 patients and IPSS-R very poor in 19 patients. If we applied IPSS-R score in WHO-AML population, we observed IPSS-R intermediate in 11 patients, IPSS-R poor in 39 patients and IPSS-R very poor in 29 patients. In all cohort population, we observed a significant difference in median OS between « intermediate + poor » group versus very poor group (12 months vs 9 months respectively, p=0.01). In MDS sub group analysis excluding AML with 20–30% of blasts, we observed no significant difference in median OS between these 2 groups (13 months vs 9 mois respectively, p=0.39). Nevertheless, we still observed a significant difference in median OS between these 2 groups in AML population (12 months vs 6 months respectively, p=0.02).
Our results suggest that AZA cancels prognostic impact of IPSS-R score in MDS patients treated by AZA. IPSS-R score could be applied in AML population and keep his prognostic impact in AML patients treated by AZA. IPSS-R score should be evaluated in larger cohort of MDS and AML patients treated by AZA in order to confirm these results.
No relevant conflicts of interest to declare.
Abstract 4936
Azacitidine (AZA) has changed the outcome of patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia with multi-lineage dysplasia (AML-MLD) unfit for intensive ...chemotherapy. AZA is a hypomethylating agent providing about 50% of responses in MDS and AML with low blast count (Fenaux et al., Lancet Oncol 2009, JCO 2010). IPSS-R scoring was evaluated in MDS and AML with 20–29% of blasts untreated patients. Conventional cytogenetic have major prognostic interest in this score (Schanz et al., JCO 2012). To date, SNP array analysis are not included in scoring system and no markers of AZA response have been identified with this analysis.
Methods: This analysis included MDS and WHO-AML-MLD (>30% blasts) patients treated by AZA in 6 centers. Genomewide single nucleotide polymorphism (SNP) analysis using SNP 6. 0 arrays (Affymetrix, High Wycombe, U. K) was performed on bone marrow (BM) samples. Patients having received ≥ 1 cycle of AZA and who had bone marrow evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered evaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML. DNAs were extracted for hybridization according to the manufacturers’ recommendations (Qiagen). Affymetrix CEL files for each sample were analyzed using the Genotyping Console software (v3. 0. 2). Genotyping was performed using Birdseed V2 algorithm. Unpaired Copy Number and LOH analysis was performed with Regional GC correction. For each patient, size of all deletions (loss) find with GC was added to have a total deletion size. The same was performed for total gain size.
Results: The study population included 51 patients: F/M: 23/28; median age 73 (range 42–88). Diagnosis at AZA onset was RAEB-2 in 19 patients (IPSS int-1 in 4, int-2 in 10, high in 5) and WHO-AML-MLD in 32 patients. Cytogenetic according to IPSS-R was good in 23, intermediate in 9, poor in 7 and very poor in 12. IPSS-R score was good in 1 patient, intermediate in 4 patients, poor in 25 patients and very poor in 21 patients. Median number of cycles was 7 (range 1–42). All patients received the approved (75mg/m2 for 7 days every 4 weeks) or a reduced AZA schedule (75 mg/m2 for 5 days every 4 weeks). Median overall survival (OS) of our cohort was 11 months. DNA samples from all patients were available for SNP analysis. In using smoothing spline Cox model analysis, we observed that relative risk (RR) of worse OS increased above 4 megabases (Mb) of total chromosomal loss size detected with SNP array. Increase of RR was found in IPSS-R intermediate, poor and very poor. OS of patients treated by AZA with more than 4 Mb of genomic loss detected by SNP array was significantly different of OS of patients with less than 4 Mb (6 months vs 14 months respectively, p=0. 0012). Negative effect of genomic loss above 4 Mb was mainly observed in IPSS-R very poor group. In IPSS-R very poor subgroup, we observed significant difference in OS between patients with more than 4 Mb of genomic loss versus patients with less than 4Mb (3 months vs 10 months respectively, p=0. 01). In our cohort, total genomic gain has no impact on OS.
Conclusion: New tools such as SNP array are not used in current practice. Therefore, prognostic impact of molecular karyotype is unclear in MDS/AML treated by AZA; our data suggest that total genomic loss superior to 4 Mb could be a worse prognosis, mainly in IPSS-R very poor patients. Impact of SNP array should be studied in larger cohort of patients treated by AZA in order to validate these results. Starczynowski et al. (Blood 2008) showed that total genomic alterations superior to 3Mb were associated with a poor OS in low-risk MDS. Taken together, these data are in favor of the use of SNP array's parameters in future prognosis scoring system.
No relevant conflicts of interest to declare.
Refractory or relapsed large B-cells lymphoma are usually treated with a high dose chemotherapy regimen followed by an autolougous stem cells transplantation. BEAM (carmustine, etoposide, cytarabine, ...melphalan) or more recently Z-BEAM (ibritumomab tiuxetan and BEAM) are commonly used regimens, but recently carmustine availability became difficult. The purpose of this study was to evaluate the feasibility and the safety of replacing carmustine by bendamustine in a new Z-BeEAM regimen (ibritumomab tiuxetan, bendamustine, etoposide, cytarabine, melphalan) prior to autologous stem cell transplantation.
This study was a retrospective analyze of six patients, with a median age of 60, treated by Z-BeEAM before autologous stem cell transplantation. We did not put in evidence any additional toxicities compared to conventional induction chemotherapy. The main toxicities were mucositis (3 grade III among 6 patients), gastrointestinal (2 grade III vomiting and 2 grade III diarrhea) and neutropenia (6 grade IV). Engraftment was successfully achieved for all patients. At the time of analysis of this study all patients were alive and in complete response based on the PET-CT evaluation.
BeEAM plus ibritumomab tiuxetan combined regimen before autologous stem cell transplantation is feasible and safe in aggressive relapsing large B-cell lymphoma.
Purpose
The pharmacokinetics of trabectedin has never been reported in patients with impaired renal function or in patients on hemodialysis.
Methods
We examined trabectedin PK in a patient on ...hemodialysis, starting trabectedin therapy at a standard dose for recurrence of a retroperitoneal myxoid liposarcoma that had occurred under immunosuppressive drugs for kidney transplant.
Results
As compared with a population with normal renal function, the study patient presented a higher
C
max
and AUC, with lower clearance, terminal half-life, and volume of distribution. The low dialysis clearance, accounting for a minor part of the total body clearance and the absence of detectable trabectedin in the dialysate samples, suggests that hemodialysis does not efficiently clear trabectedin. Trabectedin tolerance was good.
Conclusions
This case reports for the first time the feasibility of trabectedin therapy in a hemodialyzed patient. Given the rising incidence of cancer in patients with end-stage renal disease, it is crucial to provide data that improve the management of anticancer drugs in dialyzed patients.
Despite the numerous available drugs, the most appropriate treatments for patients affected by common or rare renal cell carcinomas (RCC), like those associated with the Xp11.2 ...translocation/transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) gene fusion (TFE3 RCC), are not clearly defined. We aimed to make a parallel between the sensitivity to targeted therapies on living patients and on cells derived from the initial tumor. Three patients diagnosed with a metastatic RCC (one clear cell RCC ccRCC, two TFE3 RCC) were treated with anti-angiogenesis drugs. The concentrations of the different drugs giving 50% inhibition of cell proliferation (IC50) were determined with the Thiazolyl Blue Tetrazolium Bromide (MTT) assay on cells from the primary tumors and a reference sensitive RCC cell line (786-O). We considered the cells to be sensitive if the IC50 was lower or equal to that in 786-O cells, and insensitive if the IC50 was higher to that in 786-O cells (IC 50 of 6 plus or minus 1 mu M for sunitinib, 10 plus or minus 1 mu M for everolimus and 6 plus or minus 1 mu M for sorafenib). Based on this standard, the response in patients and in cells was equivalent. The efficacy of anti-angiogenesis therapies was also tested in cells obtained from five patients with non-metastatic ccRCC, and untreated as recommended by clinical practice in order to determine the best treatment in case of progression toward a metastatic grade. In vitro experiments may represent a method for evaluating the best first-line treatment for personalized management of ccRCC during the period following surgery.
Abstract 6
GO is a potent antibody-directed chemotherapy against CD33 antigen. Two MRC and SWOG Phase 3 studies have compared standard CT alone or combined with one single GO infusion (at 3 and 6 ...mg/m2, respectively) in younger adults with AML with contradictory results (Burnett, JCO 2011; Petersdof, Blood 2009). We have shown in relapsed AML Phase 2 studies that fractionated infusion of GO 3 mg/m2 on day 1, 4 and 7 was effective and might be safely combined to standard 3+7 DNR/AraC induction (Taksin, Leukemia 2007; Farhat, AJH, accepted). Here, we report the results of the prospective open label randomized multicentric Phase 3 ALFA 0701 trial (ClinicalTrial.gov ID, NCT00927498) designed to evaluate the efficacy and safety of adding this fractionated GO schedule to standard front-line chemotherapy in older AML pts.
Eligible patients (pts) were adults aged 50–70 years old with previously untreated de novo AML. Pts were randomized to receive induction with DNR 60 mg/m2/d on day 1–3 and AraC 200 mg/m2/d CI on day 1–7, without (DA arm) or with GO at 3 mg/m2/d on day 1, 4 and 7(DAGO arm). Pts with persistent marrow blasts at day 15 received additional DNR 35 mg/m2/d on day 1–2 and AraC 1g/m2/12h on day 1–3. Pts achieving CR/CRp received two consolidation courses with DNR 60 mg/m2/d on day 1 and AraC 1 g/m2/12h on day 1–4, ± GO at 3 mg/m2/d on day 1 according to the randomization arm. The primary study objective was event-free survival (EFS). The study was designed to detect a 25% to 40% EFS gain at 3 years, (two-sided test, power 80%, type I error 5%). Secondary objectives were response rate, disease-free survival (DFS), overall survival (OS), and safety.
From March 2008 to November 2010, the required sample of 280 pts (median age, 62 years) was enrolled. Nine pts did not satisfy for inclusion criteria and were excluded from analysis. Cytogenetics was favorable (N=9), intermediate (N=177), adverse (N= 57), not done/failure (N=28). Overall, 52 pts had a favorable NPM1+ w/o FLT3-ITD genotype. The two treatment arms were well matched for all pre-treatment characteristics including age, sex, ECOG-PS, WBC, cytogenetics and molecular characteristics. CR+CRp was achieved in 220/271 pts (77%): 100/134 (75%) in the control DA arm versus 110/137 (80%) in the DAGO arm (P=0.31). There were 5/134 (4%) induction deaths in DA arm and 9/137 (6%) in DAGO arm (P=0.41). Primary resistant AML rate was 29/134 (22%) after DA versus 18/137 (13%) after DAGO (P=0.08). At 2 years, EFS was estimated at 15.6% in DA arm versus 41.4% in the DAGO arm (P=0.0018), while DFS was 18.1% in DA arm and 48.5% in the DAGO arm (P=0.0009). This significant benefit in EFS (primary objective) was observed in pts aged <65 years (P=0.035) as well as in older pts (P=0.019), and persisted after censoring the 39 pts who received allogeneic stem cell transplantation in first CR/CRp at transplant time (P=0.015). Subgroup analysis showed that EFS benefit persisted in pts with favorable/intermediate karyotype (P=0.0008) while not in those with adverse karyotype (P=0.25). Interestingly, EFS benefit was still observed when excluding favorable pts (favorable karyotype or genotype) from the comparison (P=0.0017). Finally, in the whole patient population, this gain in EFS translated into a longer OS (median, 25.4 versus 15.3 months in DAGO versus DA pts; P=0.037). Besides treatment arm, cytogenetics and favorable genotype were the only factors predictive of outcome. After adjustment on these factors, DAGO treatment remained significantly associated with longer EFS (P=0.009), DFS (P=0.003), but not OS (P=0.14). The rate of fatal adverse events at least possibly attributable to treatment was 9/134 (6.7%) in the DA and 12/137 (8.7%) in the DAGO arm (P=0.65). Prolonged grade ≥ 3 thrombocytopenia was observed in 19 DAGO pts, either after induction (N= 4) or first consolidation (N=15). Three liver VOD were observed in the DAGO arm (2 during induction, 1 during first consolidation), 2 being associated with a fatal issue. No difference was observed between both arms in the incidence of severe sepsis (DAGO 18.9%, DA 14%), as well as in the rate of intensive care unit admission during the course of therapy (DAGO 14.5%, DA 12.6%).
The addition of fractionated doses of GO (3 mg/m2/d on day 1, 4, and 7) to standard CT significantly improves EFS and to a less degree OS in AML pts aged 50–70 years old. The main toxicity observed with GO was prolonged thrombocytopenia in 19 patients and 3 episodes of VOD.
Castaigne:Pfizer/Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Gemtuzumab Ozogamicin is available in Europe as a compassionate treatment for relapsed AML. In this study patients GO was used in front-line treatment.
Treatment of osteosarcoma of the extremities consists of surgical resection preceded and followed by chemotherapy, including high-dose methotrexate or adriamycin-based protocols. When distant relapse ...occurs, therapeutic options are scarce. Trabectedin, a DNA-binding agent, is indicated for the treatment of patients with advanced soft tissue sarcomas after failure of anthracyclines and ifosfamide. In this indication, the 6-month progression-free survival is about 35-40%. Recent reports showed that some specific single nucleotide polymorphisms (SNPs) from DNA repair genes could be associated with sensitivity to trabectedin in soft tissue sarcomas.
We report our experience of 2 metastatic, heavily pre-treated osteosarcoma patients who were treated with trabectedin. Pyrosequencing analyses of tumors from both patients for several SNPs of the ERCC1, ERCC5 and BRAC1 genes were performed. Both patients showed major response to trabectedin, which was interestingly related with homozygoty of the common guanine allele of ERCC5 (G/G genotype; Asp/Asp) after pyrosenquencing analysis of tumors from both patients. This polymorphism was previously shown to be associated with better outcome in soft tissue sarcoma patients treated with trabectedin.
Homozygoty for the wild-type Asp1104 SNP of the ERCC5 gene was found in 2 cases of relapsed osteosarcoma, who responded to trabectedin.
Background: Treatment of newly diagnosed DLBCL in patients aged 65 to 80 is based on 6 to 8 cycles of R-CHOP at 14 to 21 day intervals. Recent data suggest that for patients with an IPI of 0 or 1, a ...shorter treatment may be considered. Furthermore, early negative PET-CT results after chemotherapy are an important favourable prognostic factor.
Patients and methods: We propose carrying out two cycles of R-CHOP 14 in patients aged 65 to 80 with newly diagnosed DLBCL and an IPI of 0 or 1. PET-CT will be performed on D28. If the results are normal, an R-CHOP cycle followed by an injection of ibritumomab tiuxetan 90Y will be administered. The anticipated total treatment period is 51 days. Ten patients were included from June 2007 to June 2008 (7 women and 3 men), the age-adjusted IPI was 0 and 1 in 6 and 4 cases, respectively. None of the patients had bone marrow involvement and the PS was 0 or 1 in every case.
Results: CT and PET-CT showed complete remission in 9 out of 10 patients, who therefore received the full protocol. The average age was 72 (range, 68–77). The average duration of treatment for these patients was 54 days. As regards to safety, hospitalisation or the prescription of antibiotics was not necessary in any case. No serious adverse event was reported. Mean platelet and leukocyte nadirs were 23,000/mm3 and 1,180/mm3, respectively. Two transfusions of red cell concentrates and one of platelet concentrate were necessary in one patient. To date, all patients are in complete remission.
Conclusion: The treatment regimen of 3 cycles of R-CHOP14 followed by an injection of 90Y ibritumomab tiuxetan appears to be tolerated by patients aged 65 to 80 with newly diagnosed DLBCL. Longer follow-up and the inclusion of more patients are necessary to confirm these preliminary data.
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