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  • 1
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    Eltrombopag for the Treatment of Thrombocytopenia of Low and Intermediate-1 IPSS Risk Myelodysplastic Syndromes: Interim Results on Efficacy, Safety and Quality of Life of an International, Multicenter Prospective, Randomized, Trial
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 91-91
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 91-91
    Abstract: Background: About 10% of low risk patients with myelodysplastic syndromes (MDS) experience severe thrombocytopenia. Bleeding and the scarce efficacy of platelet (PLT) transfusions drive research in novel treatments. Eltrombopag is an oral agonist of the thrombopoetin-receptor (TPO-R). Its potential in increasing platelet (PLT) counts in low risk MDS has not been evaluated. We present interim results on the efficacy and safety of eltrombopag in inducing PLT responses in patients with low and intermediate-1 International Prognostic Scoring System (IPSS) risk MDS with severe thrombocytopenia in a Phase II, multicentre, prospective, placebo-controlled, single-blind study (EQoL-MDS). Methods: Primary endpoints are safety and efficacy of eltrombopag. Secondary endpoints include changes in quality of life (QoL), PLT transfusion requirement, incidence and severity of bleeding, and survival. Inclusion criteria are adult age; PLT 〈 30 Gi/L; ECOG performance status 〈 4; ineligibility for, relapsed or refractory to other treatments; and naive to TPO-R agonists. Eltrombopag/placebo (2:1) is administered at a 50 mg daily starting dose with 50 mg increases every 2 weeks to maximum 300 mg to target PLT 100 Gi/L. Dose interruptions or reductions are required for PLT 〉 200 Gi/L or adverse events. Study design is shown in the figure. PLT response, assessed at each visit, is defined as Response if: 1) baseline PLT 〉 20 Gi/L: absence of bleeding and increase by at least 30 Gi/L from baseline; 2) baseline PLT 〈 20 Gi/L: PLT 〉 20 Gi/L and increase by at least 100%, not due to PLT transfusions; and Complete Response if PLT≥100 Gi/L and absence of bleeding. QoL scores are analysed by MDS-specific instrument, QOL-E v. 3. Results: Seventy patients (46 on eltrombopag - Arm A, 24 on placebo -Arm B) have been randomized at the time of this report. Mean age is 68.3 (SD 13.0) years, M/F 38/32. ECOG performance status was 0 in 47 cases, 1 in 16 cases, 2 in 7 cases. Ten patients had comorbidities. According to the WHO 2008 classification, 22 patients had refractory cytopenia with unilineage dysplasia, 9 had refractory anemia with ringed sideroblasts, 31 had refractory cytopenia with multilineage dysplasia (of which 15 with ringed sideroblasts), 6 had refractory anemia with excess blasts-1 and 2 were unclassified. IPSS score was low in 48 cases. Mean baseline platelet (PLT) count was 17.1 (SD 8.2) Gi/L, mean hemoglobin level 10.8 (SD 2.5) g/dL and mean white blood cell count was 5.0 (SD 3.8) Gi/L. Twenty-five (36%) patients were red blood cell transfusion-dependent. Thirty-three had a WHO bleeding scale of 1, 2 experienced mild blood loss, 4 a gross blood loss and 1 a debilitating blood loss. Fourteen patients in Arm A and 8 in Arm B had required PLT transfusions in the 8 weeks prior to randomization. Twenty-three cases (50%) in Arm A have responded versus 2 (8%) in Arm B (p=0.001). Thirty-three patients have completed at least 24 weeks of study. Median time to response was 14 days (IQR 7-46 days) at a median daily dose of 75 (IQR 50-162.5 mg). PLT count increased by mean 53.2 (SD 68.1) Gi/L (p=0.001) in Arm A versus no significant changes in Arm B by week 24. QOL-E scores at baseline and 12 weeks in 47 cases in both arms are shown in the table. There was an increase in treatment outcome index,mainly experienced in the first 3 weeks (p=0.034). Fatigue improved from baseline to 12 weeks associated with response (p=0.016). Related Grade III-IV adverse events (AE) occurred in 10 patients (22%) in Arm A and consisted in: nausea (4), hypertransaminasemia (3), hyperbilirubinemia (1), sepsis (1), pruritis (1), heart failure (1), asthenia (1), vomit (1), while in Arm B 1 patient (4 %) experienced grade 3 bone marrow fibrosis. MDS disease progression occurred in 5 (11%) in Arm A versus 2 (8%) in Arm B, p=ns. Conclusions: Preliminary data indicate that lower risk MDS patients with severe thrombocytopenia undergoing treatment with eltrombopag experience significant improvements in PLT counts accompanied by improvements in fatigue. The drug appears to be well-tolerated and not associated with MDS progression. Further follow-up is required to evaluate the impact on survival. Figure 1. Study design Figure 1. Study design Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Disclosures Oliva: Novartis: Speakers Bureau; Celgene: Other: Advisory Board, Speakers Bureau; Amgen: Consultancy. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Palumbo:Novartis: Honoraria, Other: Advisory Board. Fenaux:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.91.91
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 2
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    Sarcopenia Determined by Computed Tomography (CT) imaging is a Better Prognosis Factor Than Albuminemia or Charlson Index in Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL),
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3681-3681
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    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3681-3681
    Abstract: Abstract 3681 The prognosis of elderly patients with DLBCL remains particularly poor. The most common explanation involves co-morbidities related to advanced age, which strongly impact chemotherapy feasibility and tolerance. Sarcopenia, defined by the depletion of skeletal muscle, is known to be associated with mortality in individuals with non-malignant diseases but also to be an unfavourable prognosis factor in patients with solid tumors. Its relevance in lymphoma is still unknown. Using a simple and routinely radiological approach, we assessed for the first time the prevalence of sarcopenia and its prognosis value in a population of elderly DLBCL patients. Patients and methods: Sarcopenia was retrospectively determined in 40 DLBCL (median age 78.5 y, range 70–88 y, 19 males), characterized as follow: age adjusted IPI 0–1 = 16, 2–3 = 24; treatment by R-CHOP or R-CHOP-like regimen, n = 39; median comorbidity Charlson index = 3 (range 2–7); mean body mass index (BMI; in kg/m2) = 24.1 (40% with obesity or overweight, no patient classified as under weighted). Muscle mass was measured by analysis of stored CT images obtained for diagnostic purposes before any treatment. A lumbar vertebral landmark (L3) was selected because skeletal muscles in this region correspond to whole-body tissue quantities (Janssen et al. J Appl Physiol 2000). To calculate tissue cross sectional area (cm2), the surface of the muscular tissues was selected according to CT Hounsfield unit (range –29 to 150 for skeletal muscles). This value was normalized for stature to calculate the L3 muscle index (LMI, in cm2/m2). Results: According to the sex-specific cut-offs for LMI defined in solid tumors (55.4 cm2/m2 for men and 38.9 cm2/m2 for women), 19 DLBCL patients (47.5%,10 males) were considered as sarcopenic. Sarcopenic patients, as compared to non sarcopenic patients displayed a similar level of albuminemia, Charlson index, aaIPI, weight loss, BMI, performance status or B symptoms. By contrast the mean age was 81y in the sarcopenic group and 77y in the non sarcopenic group (p=0.003). With a median follow-up of 39 months, the 2y overall survival in the sarcopenic population was 38% as compared to 70% in the non-sarcopenic group (HR = 0.25; CI95%, 0.1–0.70; p=0.01). The prognostic value remains significant in the subgroup of patients younger than 80y (HR=0.12; CI95% 0.03–0.53; p=0.005). Mortality was mainly related to progressive disease in the sarcopenic group. Hypoalbuminemia tend to be correlated to an unfavourable outcome (p=0.06). In multivariate analysis including albuminemia and aaIPI, sarcopenia remains predictive of the outcome (p=0.03). LMI was also calculated after treatment at least 6 months following initial CT scan (n =30, mean interval =11.8 months, range 6.3–19.2). 11 patients (36%) displayed a reduction ( 〉 5%) and 19 patients (64%) an increase ( 〉 5%) or a stabilisation of the LMI. Conclusion: Sarcopenia assessed by CT scan appears as a strong prognosis factor in elderly DLBCL patients, more relevant than usual anthropometrical measures or usual prognostic factors. A prospective multicentric study is currently ongoing to validate these results and to determine if the sarcopenic status should be integrated in future strategies to treat elderly patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3681.3681
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 3
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    Therapy Related APL (tAPL). Prospective Analysis of Etiological Factors In Recent Cases, and Comparison with De Novo Cases
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2171-2171
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    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2171-2171
    Abstract: Abstract 2171 Background: Our group (JCO, 1992 10:1430; JCO 2003,21:2123) and others have reported tAPL to occur at increased frequency (from 5% of APL between 1984 and 1993 to 22% between 1994 and 2000 in our experience), generally less than 3 years after a primary neoplasm (mainly breast carcinoma) treated with the combination of anthracyclines (anthr) and cyclophosphamide (CY), radiotherapy (RT) and less often VP 16, but our last published series analyzed patients (pts) diagnosed before 2001. In addition, characteristics and outcome of tAPL are considered similar to those of de novo APL, but all reported comparisons were retrospective. We took advantage of our current multicenter APL 2006 trial, which includes both de novo and tAPL, to analyze possible recent changes in etiological factors of tAPL cases, and to prospectively compare them with de novo APL. Methods: In APL 2006 trial, pts 〈 70 years with WBC 〈 10 G/l, received ATRA+Idarubicin+AraC for induction, followed by 2 consolidation courses with (randomized) Ida+AraC, ida+ATO or Ida+ATRA. Pts 〈 70 y with WBC 〉 10 G/l, received the same induction treatment, followed by 2 consolidation courses with (randomized) ida+AraC or Ida+AraC+ATO. Pts 〉 70y received the same induction course with reduced dose of Ida and two consolidation courses (Ida+ATO and ATO+ATRA). All patients received 2 y maintenance therapy combining continuous 6MP+ MTX and intermittent ATRA. Results: Between Nov 2006 and March 2010, 280 pts entered the trial, including 42 (15 %) tAPL. By comparison to our tAPL diagnosed before 2001 (JCO 2003, 21, 2123) the primary tumor was less often breast carcinoma (35.7% vs 56.6%, p=0.03), and more often prostate carcinoma (26.2% vs 4.7%; p 〈 10-3) and other solid tumors (45.2% vs 18.8% p=0.02). Treatment of the primary tumor, in APL 2006 trial cases and tAPL diagnosed before 2001, respectively, included chemotherapy (CT) alone in 21.4% vs 27.3% pts (p= 0.535), RT alone in 40.5% vs 25.4% pts (p= 0.077) and RT+CT in 28.6% vs 47.2%(p= 0.044), and, in pts who received CT, at least one alkylating agent in 90.5% vs 86% pts (p=ns), at least one topo II inhibitor in 61.9% (including anthr in 47.6% and VP 16 in 14.2%) vs 77% pts (including anthr in 37.9% and VP 16 in 24.1%), and including mitoxantrone in 0% vs in 36.4% pts (p 〈 10-3). Hormone therapy was used in 42.9% (including antioestrogen (n=7), aromatase inhibitors (n=7) GnRH analogues (n=4), and anti androgens (n=4)) vs 24.5% (no details available), resp. Median interval from primary tumor to tAPL was 48 months (range 6.9 to 299) in tAPL included APL 2006 trial, compared to 25 months in our previous tAPL series. In APL 2006 trial, characteristics of tAPL were similar to those of de novo APL, with regards to WBC count (21.4% WBC 〉 10 G/l vs. 22.3% in de novo APL, respectively) and M3 variant (14% in the 2 groups). However, tAPL were older (mean 60.2y vs 48.7y in de novo cases, p 〈 0.0001) and had a higher frequency of bcr3 breakpoint (36% vs 54%, p=0.015). The CR rate was 97.6% (41/42) in tAPL and 93.4% in de novo APL (p=0.48). The 18-month cumulative incidence of relapse was 0% and 1.2% in tAPL and de novo APL respectively (p=0.43). 18 months OS was 96.4% and 97.0%, respectively (p=0.83, log-rank test). The 18 month rate of death in CR was 3.6% in both tAPL and de novo APL (p=0.97), Conclusion: In this series of recently diagnosed tAPL, by comparison to our tAPL diagnosed before 2001, the primary tumor was less often breast carcinoma and more often another solid tumor (especially prostate). A combination of CT and RT had been less often used, hormone therapy more often, and mitoxantrone had no more been used. Prospective comparison with de novo APL included in the same trial showed tAPL to be characterized by older age and more frequent bcr3 breakpoint, but there were no differences in outcome between the 2 subgroups Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2171.2171
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 4
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    The Revised IPSS (IPSS-R) Predicts Response To Erythropoietic Stimulating agents (ESA) In Pts With Classical IPSS Low Or Intermediate-1 (int 1)- MDS: A Joint Retrospective Study Of The GFM, Düsseldorf Registry and Fism
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 2761-2761
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2761-2761
    Abstract: Introduction The “classical” IPSS, based on cytogenetics, marrow blast percentage, and number of cytopenias, has played a major role in prognosis assessment in MDS. The recently published revised IPSS (IPSS-R), refines the original IPSS prognostic value (Greenberg et al, Blood 2012). However, its prognostic value for response to ESA has not been assessed. We analyzed it retrospectively in 456 IPSS Low-/Int-1-risk MDS patients (pts) treated with ESA in France, Germany and Italy. Results Those 456 pts had serum EPO 〈 500mU/ml and Hb≤10g/dl, and had received ESA (EPO alfa or beta 40000-60000 IU/week, or darbepoietin 150 - 300µg/week) for at least 12 weeks. In addition to IPSS-R parameters, age, sex, serum EPO level, serum ferritin (SF), and RBC transfusion requirement before ESA onset were assessed for response to ESA (based on IWG 2006 criteria), and overall survival (OS) from ESA onset. Characteristics of the 456 pts at ESA onset are listed in Table 1. 71% of the pts had never received RBC transfusions, with a median Hb level of 9.3g/dl (range 7.0-10) , and 29% pts had received at least 4 RBC concentrates/8wks before ESA onset (with a maximum of 12). Median SF was 357ng/ml and serum EPO 60mU/ml (range 6-483). IPSS was low in 55% and intermediate-1 in 45% pts. IPSS-R was very low in 15%, low in 61%, intermediate in 19% and high in 4% of the pts. 303 (61%) pts had an erythroid response (ER), including 72% and 52% of low and int-1 risk pts respectively (p=0.001). Using IPSS-R, 85%, 68%, 48% and 31% of pts had ER in the very low, low, intermediate and high risk group respectively (p 〈 0.0001). Other prognostic factors of ER, in univariate analysis, included individual IPSS-R parameters analyzed according to IPSS-R thresholds (Hb level, platelet count, ANC, marrow blast %, cytogenetics) serum EPO level, SF (variables tested as continuous variables) and previous RBC-transfusions. In multivariate analysis, IPSS-R, serum EPO, and SF remained significantly associated with ER (p 〈 0.0001, p=0.002 and p 〈 0.0001 respectively). Applying 1 point to each of the following unfavorable variables of ER: serum EPO 〉 200mU/ml (=1), SF 〉 350 ng/ml (=1), IPSS-R (very low=0, low=1, intermediate=2 and high=3), yielded a score ranging from 0 to 4, with ER rates of 85%, 80%, 64%, 40% and 20% respectively. As expected, IPSS-R also had strong prognostic value for OS (not shown). Conclusion In this patient cohort with overall favorable prognostic factors of response to ESA according to the Nordic score (ie serum EPO 〈 500 mU/ml and no or limited transfusion dependence, Hellstrom-Lindberg et al BJH 2003), IPSS-R alone, and even better, a score 〉 =3 (using IPSS-R, serum EPO and SF) proved useful to identify pts with low response to ESA, who also have worse OS and may require alternative treatments (Kelaidi et al, Leukemia 2013). Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.2761.2761
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 5
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    Comparison of Clinical Characteristics, Plasma Cytokine Signature, Cytokine Gene Polymorphisms and Outcome Between EBV Positive and Negative Hodgkin Lymphoma: a Study of the Groupe Des Lymphomes De l'Adulte (GELA)
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3884-3884
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    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3884-3884
    Abstract: Abstract 3884 Background: Hodgkin Lymphoma (HL) has a remarkable pathogenesis with rare neoplastic cells surrounded by numerous reactive cells that interact with cytokines, chemokines and soluble receptors. EBV is found in about 40% of HL. Recent clinical series showed that prognostic between EBV-positive and negative could be different especially in patients older than 50 years old, with a worse prognosis for patients with EBV-positive tumors (Diepstra et al. JCO 2009). Gene expression profile analysis of HL tumors are also in favor of different pathogenesis between EBV-positive and negative tumors. In this context, we assessed whether plasma cytokine pattern and cytokine gene polymorphisms could be different regarding EBV status and compared the clinical characteristics and outcome of patients according to EBV status in a series of 242 HL patients. Patients and Methods: the GELA conducted between 1998 and 2002, a prospective study to assess the prognostic role at diagnosis of plasma levels of TNFA, its soluble receptors TNF-R1, TNF-R2, and IL-10, IL-6, IL-1B, IL-1Ra, sCD30 (Casasnovas et al. JCO 2007). This study was also designed to investigate the role of polymorphisms (SNP) in cytokine genes of IL10 (Four SNPs), TNFA, IL6, IL1B, IL1RN, INFG, CCL17 and IL12. EBV status of classical HL samples could be obtained retrospectively for 242 patients. Results: EBV status was obtained according to the immunohistochemistry detection of latent membrane protein-1 (LMP-1) in 186 patients (77%), to EBER in situ hybridation results in 48 patients (20%) or others techniques in the 8 remaining patients (3%). EBV status was considered as positive and negative for 53 (21%) and 189 (79%) patients, respectively. Comparison of clinical characteristics between EBV-negative and positive HL showed some differences in term of sex-ratio and histological subtypes with a higher proportion of male in EBV-positive cohort (81% vs. 54%, P 〈 .01) and less nodular sclerosis subtypes (74% vs. 85% P = .05). Erythrocyte sedimentation rate and white-cell count were more frequently increased in EBV-negative population but the distribution of prognostic categories according to the Hasenclever score was not different between the two cohorts. The TNFA and TNF-R2 plasma levels were significantly higher for EBV-positive compared to EBV-negative HL (P = .03) but no difference was observed for others cytokines (TNF-R1, IL-10, IL-6, IL-1Ra, sCD30). For the eleven studied SNPs, no difference in term of genotype distribution was observed between EBV-positive and negative tumors. The 6-year overall survival (OS) (91% vs. 88% P = .3) and progression free survival (PFS) (81% vs. 79% P = .3) were not statistically different between the EBV-negative and positive cohorts. Analysis of outcome by age groups, showed a non-significant trend for a worse 6-year OS (72.1% vs. 58.3% P = .14) and 6-year PFS (57.2% vs. 48% P = .42) for EBV-positive HL after 50 years old with a similar proportion of EBV-positive and negative HL tumors before and after 50 years old. Conclusions: In this study, we confirm difference of histological subtype distribution between EBV-positive and negative HL. A difference of plasma levels of TNFA and TNF-R2 was observed suggesting a different inflammatory profile between EBV-positive and negative EBV HL but genotype distribution of germline cytokine gene polymorphisms was not different. In this cohort of HL with a global favorable outcome, a trend for a worse prognosis became apparent for older patients with EBV-positive HL. Disclosures: Salles: Roche: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3884.3884
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
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    MDS with Isolated Trisomy 8. a Type of MDS Frequently Associated with Myeloproliferative Features? A Report from the GFM
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 2881-2881
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    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2881-2881
    Abstract: Introduction Isolated trisomy 8 is a frequent cytogenetic abnormality in MDS, but hematological characteristics of MDS with isolated trisomy 8 have not been reported in detail. Patients and Methods This was a retrospective analysis of cases of MDS with isolated trisomy 8 diagnosed in 6 French centers of the Groupe Francophone des Myélodysplasies (GFM) between 2003 and 2013. Only patients with isolated trisomy 8 diagnosed as MDS or MPN/MDS (other than CMML) according to WHO were eligible, excluding AML, well characterized MPN (PV, ET) and CMML. Myeloproliferative (MP) features were defined by repeated presence (in the absence of infection) of one of the following: WBC 〉 10G/L, circulating immature granulocytes (myelemia ) 〉 2%, or palpable splenomegaly. Results 103 patients with isolated trisomy 8 were identified, with a median age of 75 years, and M/F 1.7. At diagnosis, median WBC count was 4.1 G/L, with WBC ≥ 10 G/L in 13 patients (12.6 %), myelemia ≥ 2% in 27 patients (26.2 %), palpable splenomegaly in 9 patients (8.7 %). WHO diagnosis included 20 RA, 2 RARS, 22 RCMD, 1 RCMD-RS, 1 RCUD, 21 RAEB-1, 18 RAEB-2, 7 MDS-U, 10 MDS/MPN, 1 hypoplastic MDS. IPSS was intermediate 1 (72.2 %), intermediate 2 (19.6 %), high (8.2 %) ; IPSS-R was low (37.1 %), intermediate (29.9 %), high (22.7 %), very high (10.6 %). MP features were found in 50 patients (48.5 %): 31 at diagnosis, 19 during evolution (in patients without MP features at diagnosis). Bone marrow morphological features could be reviewed in 15 MP cases, showing hypercellular marrow in 60 % cases, granulocytic hyperplasia (E/G 〈 0.25) in 53%, marked neutrophil hypogranularity in 87% and abnormal chromatin clumping in neutrophils in 53 %. Somatic mutations were studied in 31 patients on diagnostic samples (16 MP and 15 non MP) for 27 most frequently mutated genes in MDS and MPN: ASXL1, CBL, DNMT3A, ETV6, EZH2, IDH1, IDH2, JAK2, cKIT, KRAS, NRAS, MPL, PHF6, PTPN11, RIT, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, ZRSR2, FLT3-TKD, FLT3-ITD, NPM1 (FLT3-TKD, FLT3-ITD and NPM1 were studied in only 15 patients). Mutations were seen, for MP cases, in ASXL1 (64%), EZH2 (50%), TET2 (40%), RUNX1 (33%), SRSF2 (27%), DNMT3A (15%), JAK2 (14%), IDH2 (14%), NRAS (8%), SF3B1 (9%), U2AF1 (8%); for non MP cases in ASXL1 (33%), SRSF2 (27%), SF3B1 (27%), TET2 (20%), DNMT3A (13%), JAK2 (13%), RUNX1 (13%), EZH2 (7%), IDH2 (7%), ZRSR2 (7%), NRAS (0%). In spite of a trend for more mutations of ASXL1 (p=0.128), and EZH2 (p=0.053) in MP forms, the difference with non MP forms was not significant, possibly due to small patient numbers. 40 patients received an HMA (AZA in 36, DAC in 4) and 27.3% responded (4 CR, 1 PR, 1 marrow CR, 3 HI), including 11.7% of MP cases and 43.8% of non MP cases (p=0.057). 5 patients received intensive chemotherapy (with 2 CR). 42 (40.8%) received an ESA, with 60% responses, including 50% in MP and 73% in non MP patients (p= NS).10 (9.7%) received hydroxyurea. With a median follow up of 30 months, progression to AML was seen in 26% and 18.9% in MP and non MP patients, respectively (p= NS). Median survival was 35 months in the whole cohort, without difference between patients who, at diagnosis had MP features and no MP features (35 months for both). Conclusion Myeloproliferative (MP) features were found at diagnosis or during evolution in our experience in about 50% of MDS with isolated trisomy 8, a finding not previously reported, to our knowledge, and suggesting that some of those patients may have to be reclassified among MDS/MPN. The subset of patients with MP features tended to have a higher frequency of ASXL1 and EZH2 mutations (findings that will have to be confirmed on larger patient numbers), and seemed to respond poorly to HMA, although its survival was not lower than that of non MP forms in our experience. Disclosures Park: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Celgene: Research Funding. Fenaux:AMGEN: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.2881.2881
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 7
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    Treatment of Advanced CMML by Azacitidine (AZA) In a Compassionate Program. the GFM Experience In 38 Patients (pts)
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4023-4023
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    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4023-4023
    Abstract: Abstract 4023 Background: Treatment of CMML remains difficult, with no drug having shown a clear clinical benefit. AZA has demonstrated a survival benefit in higher risk MDS, in a study that included a small number of CMML (Lancet Oncol, 2009). Several small series of CMML treated by Decitabine (Wijermans, Leuk Res. 2008, Aribi A, Cancer. 2007 and Kantarjian H, Blood. 2007), and AZA (Scott, Br J Haematol. 2010) have been reported, but pts were often very heterogeneous in terms of risk factors and treatment, while in the AZA paper, patients also received etanercept in combination. Methods: The French health agency (AFSSAPS) designed, between 2004 and 2008, a pt named program (ATU) of AZA in higher risk MDS and poor risk AML. 38 pts with CMML or AML arising from CMML included in this program before April 08 and having completed ≥ 1 cycle of AZA (75 mg/m2/d during 7 days every 28 d) are analysed here. As CMML has features of both MDS and MPD, its risk factors are somewhat composite. Based on our previous experience (JCO 1988 6:1417, Blood 1996 88:2480) and on IPSS, pts with WBC 〈 13 G/L were classified according to IPSS, and, in those with WBC 〉 13 G/L, risk factors were based on: marrow blasts≥5%, Hb 〈 10g/dl, plts 〈 100G/l, abnormal cytogenetics, splenomegaly 〉 5cm below costal margin (SMG 〉 5cm) and extramedullary disease (EMD). Response was evaluated according to IWG 2006 criteria in pts with WBC 〈 13G/L, also took into account “proliferative” features of CMML (splenomegaly, increased WBC and blood monocytes, extra medullary disease) in pts with WBC 〉 13G/L, and IWG-AML 2003 criteria for AML. Results: median age was 71 y (range 50–87), M/F: 28/10. Median interval from diagnosis to treatment was 22 months (range 0.2–74 months). Previous treatment was low dose chemotherapy (CT) (n= 10, low dose Arac n=2, HU n=8), Intensive CT (n=12), allogeneic SCT (n=1), ATO (n=2). At inclusion, 9 pts had CMML-1, 17 CMML-2 and 12 AML secondary to CMML according to WHO. Karyotype was normal (n=16), isolated –7/7q- (n=2), +8 (n=1), del 20q (n=1), complex (n=2), -Y (n=2) and a failure (n=2). In the 14 CMML with WBC 〈 13G/L, IPSS was low in 1, int-1 in 3 pts, int-2 in 8 pts and High in 2 pts. In the 12 CMML with WBC 〉 13G/L, 10 had more than 3 risk factors defined in Blood 1996 88:2480. The median number of cycles of AZA administered was 4 (range 1–26). 6 pts received also HU during the first cycles to reduce WBC count. 9 pts received less than 4 cycles due to early death (n=4), progression (n=3) and haematological toxicity (n=2). 20 pts (53%) responded including 9 CR, 3 marrow CR,8 HI-E and 1 partial remission. 19 (68%) of the 28 pts who received more than 4 cycles responded, including 9 CR, 3 mCR, 1 PR and 6 HI. Of the 26 CMML without AML progression, 15 (58%) responded (7 CR, 2 marrow CR and 6 HI-E). Of the 12 AML arising from CMML, 5 (42%) responded (2 CR, 1 marrow CR, 1 PR and 1 HI-E). Median number of cycles of AZA to achieve best response was 4 (range 3–12). Age (p=0.38), WBC count (p=0.76), Hb level (p=0.987), platelet count (p=0.07), blood monocytes (p=0.4823), Sex (p=0.28), CMML 1 vs 2 (p=0.48), splenomegaly (p=0.7), normal karyotype (p=1), -7/del7q(p=0.65), concomitant treatment with HU (p=0.6), 〉 3 risk factors in CMML with WBC 〉 13 G/l, and previous treatment (p=0.506) had no impact on response. 9 of the 20 responders relapsed after a median of 10.6 months (range 3–23), including 4/9 (44%), 1/3 (33%), 0/1, 4/8 (50%) of the pts who had achieved CR, mCR, PR and HI respectively, 10 remained responders after a median of 26 months (16-35) and 1 pt with HI died without relapse. Median overall survival (OS) was 24 months in CMML compared to 7 months in AML arising from CMML (p= 0.0081). Presence of splenomegaly, WBC 〉 13 G/l, previous treatment (excluding ESA), Sex, -7/del7q and normal karyotype had no impact on OS. Conclusion: In this series of CMML which had on average more unfavourable prognostic factors than in previous series of CMML treated with Decitabine or AZA (10/14 with WBC 〈 13G/L were IPSS int 2 or high, 10/12 with WBC 〉 13 G/L had at least 3 risk factors, and 12 had progressed to AML), AZA showed clear efficacy, but mainly in pts who had not progressed to AML. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    DOI: 10.1182/blood.V116.21.4023.4023
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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    Outcome of Lower Risk Non Del 5q MDS after Failure of Erythropoiesis Stimulating Agents (ESA), and Impact of Post-ESA Treatment on Survival: A Retrospective European Study
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1665-1665
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    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1665-1665
    Abstract: Background : Most non-del 5q lower risk MDS patients (pts) are first treated with ESA, with about 50% (generally transient) responses, and second line treatments (TX) including hypomethylating agent (HMA), Lenalidomide (LEN) and investigational drugs are then often proposed, but their effect on overall survival (OS) is unknown. In a previous work on 253 such pts, we found worse OS with early failure to ESA, i.e. primary resistance (RES) or relapse (REL) 〈 6 months after ESA onset (Kelaidi, Leukemia, 2013), but only few pts had received, after ESA failure, TX other than RBC transfusions. In the present study, we gathered non-del 5q lower risk MDS treated with ESA from several EU MDS cooperative groups, and analyzed their outcome after ESA failure, and the effect of second line TX on survival. Methods : 1611 IPSS low and int-1 (lower risk) non del 5q MDS pts included in the French (GFM), Italian (FISM), Spanish (GESMD), Greek, Düsseldorf and Munich registries between 1997 and 2014, and treated by ESA were studied. Survival was assessed from failure of ESA (i.e. from primary failure evaluated after 12 to 24 weeks of ESA treatment, or from relapse after a response). Progression at ESA failure was defined upon progression to a higher IPSS-R class at ESA failure as compared with ESA onset. Results : At ESA onset, the 1611 pts were reclassified by IPSS-R in 16% very low, 54% low, 13% int, 6% high, 1% very high and 10% ND. HI-E (using IWG 2006 criteria) to ESA treatment was 66.9%, and the median duration of response was 15 months. The cohort of 1038 pts with ESA failure included 521 RES and 517 REL. Median OS was 4.2 years in REL and 3.7 years in RES pts (p=0.56), and no significant difference was seen, even after restricting the analysis to very low and low IPSS-R pts (p=0.81), or when analyzing "early" vs "late" failures, with cut-off points at 6 or 12 months, as we previously reported (Kelaidi, Leukemia, 2013). 336 (32%) pts received second line treatment (TX2) other than RBC transfusions, including HMA in 88 pts, LEN in 169 pts, and other TX (OT) in 79 pts (including 11 chemotherapy, 17 thalidomide, 11 immunosuppressors (ATG, cyclosporine), or investigational drugs), with response rates of 46%, 39% and 33% respectively (p=0.4). 87 pts had a third line TX (mostly a new drug, but also 7 pts who received HMA after LEN, and 33 pts LEN after HMA). Pts treated with LEN as TX2 were younger (median age 70 vs 75 for BSC, and 70 for HMA p 〈 10-4), had more RARS (67% vs 28% for BSC and 27% for HMA, p 〈 10-4), while pts treated with HMA as TX2 had more RAEB-1 (34% vs 10% for BSC and 12% for LEN, p 〈 10-4) and more high and very high IPSS-R at onset of TX2 (48% vs 4.6% for BSC and 3.1% for LEN, p 〈 10-4). Median OS for pts receiving BSC, LEN, HMA and OT as TX 2 was 4.3y, 3.7y (HR 1.1 [0.81-1.50] p=0.5), 2.1y (HR 1.59 [1.12-2.72] , p=0.01) and 2.2y (HR1.17 [0.81-1.68], p=0.41) respectively (Figure). However, in a multivariate analysis adjusted on age, gender, and IPSS-R progression at ESA failure, OS difference became not significant. Analysis of AML progression in the different TX2 groups is currently being finalized. C onclusion: In this large multicenter retrospective cohort of non-del 5q lower risk MDS pts having failed ESA treatment, OS from failure was similar in RES and REL pts, contrary to our previous smaller experience. About 1/3 of the pts received second line treatments other than RBC transfusion, mainly LEN or HMA. However, none of those treatments was able to improve OS compared to BSC. Newer treatments are required in this situation, possibly including allogeneic SCT in younger pts. Figure 1. OS since ESA failure according to TX2 (Simon-Makuch method). Figure 1. OS since ESA failure according to TX2 (Simon-Makuch method). Disclosures Park: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Celgene: Research Funding. Off Label Use: Lenalidomide in non del 5q MDS. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Cheze:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wattel:PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Fenaux:Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1665.1665
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 9
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    Outcome Analysis of High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma: A Francophone Society of Bone Marrow Transplantation and Cellular Therapy Study
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 3458-3458
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    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3458-3458
    Abstract: Background Many patients with relapsed or refractory Hodgkin's lymphoma (HL) undergo high-dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT). However, most large reports include patients treated in the 90's. We aimed to analyze the outcome of a HL patients treated in the last decade with HDC and auto-SCT in a large cohort study. Patients and methods In the setting of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, we retrospectively analyzed 1987 consecutive adult patients (age 〈 65 years) with biopsy-proven HL who received a first auto-SCT between 2003 and 2014. Results Median age at auto-SCT was 33.7 years (range, 18-65) and 60% patients were male. Disease status at transplant was complete remission in 1040 patients (52%), partial response in 727 (37%) and progressive disease in 220 (11%). The main conditioning regimen was BEAM (Carmustine-Etoposide-Cytarabine-Melphalan, n=1497). At one month, cumulative incidence of neutrophil engraftment was 97.6% (95% CI 96.8-98.2), whereas cumulative incidence of death without engraftment was 0.2% (95% CI 0.07-0.5). After a median follow-up of 16.4 months (IQR, 4.4-47.2), 3-year overall survival (OS), disease-free survival (DFS), cumulative incidences of relapse (IR) and non-relapse mortality (NRM) were 80.4% (95% CI 78.1-82.9), 59% (95% CI 56.1-62), 35.9% (95% CI 33.1-38.7) and 5% (95% CI 3.9-6.4), respectively. There was no significant difference in terms of outcome between patients treated during the time period 2003-2008 and 2009-2014. 3-year OS and DFS were 70.5% and 43.7% in patients with progressive disease at transplant, 75% and 52.1% in patients in partial response, 87.2% and 67.8% in patients in complete remission (p 〈 0.0001 and p 〈 0.0001, respectively). Male had a decreased 3-year OS compared to female (HR 1.46, 95% CI: 1.15-1.84; p=0.002). Age ≥ 35 years was associated with a higher NRM (HR 1.67, 95% CI: 1.06-2.65; p=0.029) but a better PFS (HR 0.77, 95% CI: 0.65-0.91; p=0.002). Overall, patient age did not significantly influence OS (p=0.19). Primary refractory or multiple relapsed patients had a worse outcome than the others. A number of previous treatment lines ≥ 3 negatively influenced OS (HR 1.91, 95% CI: 1.42-2.58; p 〈 0.0001), PFS (HR 2.03, 95% CI: 1.60-2.56; p 〈 0.0001), IR (HR 1.90, 95% CI: 1.48-2.45; p 〈 0.0001) and NRM (HR 3.17, 95% CI: 1.69-5.96; p=0.0003). Cumulative incidence of NRM reached 9% at 3 years in these patients. Finally, patients who relapsed after auto-SCT (n=494) had a 3-year OS of 52.8% (95% CI 47.7-58.3). Conclusion In conclusion, HDC followed by auto-SCT is highly efficient in relapsed HL patients. However, relapse occurs in over 40% of patients 〈 35 years old or with partial response at transplant and in over 50% of patients with progressive disease at transplant or ≥ 3 previous treatment lines. Additional data are being collected to better identify which high-risk patients could benefit from post-transplant immunotherapy or tandem auto-allo transplant. Disclosures Brice: Roche: Honoraria; Bristol Myers-Squibb: Honoraria; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Seattle Genetics: Research Funding; Gilead: Honoraria. Salles:Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria. Peffault De Latour:PFIZER: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.3458.3458
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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    Assessment of Cardiac Iron Overload in Chonically Transfused Patients with Thalassemia, Sickle Cell Anemia, and Myelodysplastic Syndromes
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 2151-2151
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    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2151-2151
    Abstract: Background. Cardiac iron overload is the major cause for death in regularly transfused thalassemic (Thal) patients. Its impact in myelodysplastic syndrome (MDS) patients is debated. Heart seems to be spared in regularly transfused patients with sickle cell anemia (SCA), which is supposed to be related to a later onset on transfusions and to the use of erythrocytapheresis rather than simple transfusion. Our aim was to assess the prevalence of cardiac iron overload, defined as a T2*cardiovascular magnetic resonance (MR) 〈 20ms, and to look for predisposing factors. Patients and methods. Patients were enrolled if they were regularly followed in a center where the exact number of erythrocyte concentrates (EC) could be obtained, had received in the previous year more than 8 EC, were older than 6 years (limit for MRI without sedation), had no known heart disease related to another pathology, and had given informed consent. All patients underwent 1.5T myocardial T2*MR imaging after validation of the procedures in the different sites. Assessment of Liver Iron Content (LIC) used two signal intensity ratio of gradient echo imaging (R2*) MRI protocols. Serum Non-Transferrin Bound Iron (NTBI) was measured by the FeROSTM eLPI kit, and serum hepcidin by LC-MSMS. Results. 20 Thal, 41 SCA and 25 MDS patients were evaluable. We divided SCA in 2 groups, according to the procedure recorded at the time of the study, manual exchange transfusion (G1, N = 30 patients), or erythrocytapheresis (G2, N=11 patients). We found cardiac overload in 0, 3 (15%), and 4 (16%) of SCA, Thal, and MDS patients respectively. Serum ferritins at beginning of chelation were not statistically different in all categories of patients, as well as Ferritin and LIC at the time of the study. Increased LIC and abnormal T2* were associated in Thal and MDS patients (p=0.04), with no correlation between abnormal T2* and parameters of transfusion and chelation. Plasmatic iron level was increased in Thal and MDS patients but remained at normal range in SCA patients. NTBI level was high in Thal and MDS but completely absent in SCA groups. The major discrepancy was in the values of hepcidin, which were collapsed in Thal, at normal range in SCA, and highly elevated in MDS patients. Discussion and conclusion. We confirm that SCA patients are relatively protected from cardiac iron overload. This results probably from massive consummation of iron through effective erythropoiesis, making toxic free iron (NTBI) less available in the circulation. In addition, since iron overload in SCA results from a massive outflow of hemoglobin (Hb) due to intravascular hemolysis and transfusion, the heme/Hb-bound iron must be efficiently handled in liver macrophages, limiting its release in the bloodstream. In Thal patients, underlying defects in erythropoietic processes, together with low hepcidin that stimulates intestinal iron absorption and increases NTBI, must provoke more organ damages. Hepcidin levels were high in MDS patients, suggesting that transfusion-dependent iron overload was a more effective regulator of hepcidin production than dyserythropoiesis. The % of T2* 〈 20 ms we observed in MDS patients (16%) was quite comparable with previous publications. Finally, we observe that, in opposition with previous reports, SCA patients undergoing eythrocytapheresis may experience severe iron overload and need iron chelation. Table 1. Thal SCA G1 SCA G2 MDS p Age at beginning of transfusion (yrs) 8.5[0-45] 7[0-45] 16.5[1-55] 66[38-83] 〈 0.001 Duration of transfusion (yrs) 10[1-39] 7[1-22] 10.5[0-25] 3[1-10] 〈 0.001 N EC since diagnosis 359[21-1360] 139[24-791] 201[14-888] 77[16-544] 0.0005 N CE/yr 24[8-67] 21[4-62] 35[17-58] 27[7-65] 0.09G1vsG2=0.03 % patientschelated 95 90 72.7 72 0.12 Age at beginning of chelation (yrs) 11[1-48] 9[2-47] 18[6-31] 68[38-84] 〈 0.0005 Ferritin at beginning of chelation (ng/ml) 1148[713-2400] 2075[448-3670] 1500[905-2804] 2398[482-5140] 0.22 N T2* 〈 20 ms 3(15%) 0 0 4(16%) 0.01 LIC (mg/g d.w.) 10.4[0.8-20.2] 10.7[0.8-37.1] 14[0.8-19.7] 15.2[3.0-45.3] 0.29 Plasmatic iron(μmol/l) 36.9[31-57] 22.5[6-42.2] 21[13-46] 38.2[11.9-72] 〈 0.001 NTBI (mg/ml) 7.1[0-31.1] 0[0-18.3] 0[0-12.4] 4.45[0-25.5] 0.0005 Ferritin (ng/ml) 870[169-4339] 2739[393-5596] 2404[33-20030] 1611[223-6813] 0.08 Hepcidin (ng/ml) 1.35[0-12.3] 9.95[0-67.9] 2.10[0-52.4] 36.35[3-143.2] 〈 0.001 Deferasirox dosage 〈 0.5 μg/ml 3/8(38%) 3/10(29%) 3/5(60%) 0/11(0%) 0.03 Disclosures De Montalembert: Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau.
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    ISSN: 0006-4971 , 1528-0020
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    DOI: 10.1182/blood.V126.23.2151.2151
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    Publisher: American Society of Hematology
    Publication Date: 2015
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