Prognostic Factors For Response Research Articles

The Danish experience with trabectedin treatment for metastatic sarcoma: Importance of hyponatremia

Background. Trabectedin was in Europe approved for treatment of metastatic soft tissue sarcoma (STS) in 2007 based on results of a phase II study with relatively few patients. The purpose of this nationwide retrospective study was to assess efficacy and safety of using trabectedin in the entire unselected cohort of patients with metastatic sarcoma and to test known, as well as new prognostic factors that may affect overall survival (OS).Patients and methods. Between January 2008 and April 2013, 117 patients were treated with trabectedin for metastatic sarcoma in the three specialized sarcoma centers in Denmark. Known prognostic factors such as age, gender and performance status, the histopathology as well as other new factors such as response to previous chemotherapy and hyponatremia were tested.Results. Median age was 59 years. Lipo- and leiomysosarcomas (L-sarcomas) represented 43% of the cases and 18% had hyponatremia before the start of trabectedin. The median number of previous lines of chemotherapy was two (range 0–6) and the median number of chemotherapy cycles given before trabectedin was nine (range 0–85). The median number of trabectedin cycles was three (range 1–17). The median OS for the whole cohort was seven months. Poor performance status, non-L-sarcomas, and hyponatremia were statistically significant adverse prognostic factors with median survival of: 4, 5, and 2 months compared to 9, 12 and 13 months, respectively. Moreover, having achieved clinical benefit [complete response (CR), partial response (PR) or stable disease (SD)] from previous chemotherapy was a favorable prognostic factor for response to trabectedin. In multivariate analysis hyponatremia was the only independent significant poor prognostic factor affecting OS.Conclusions. This retrospective study confirmed the previously published safety and efficacy of trabectedin in patients with metastatic sarcoma and showed hyponatremia to be a strong independent statistically significant poor prognostic factor.

Abnormal Free Light Chain Ratios are Significantly Associated with Clinical Progression in Chronic Lymphocytic Leukemia

Serum Free Light Chains (FLC) have prognostic significance in diverse plasma cell dyscrasias. Although monoclonal protein secretion is a typical feature of these diseases, it can also be detected in other B cell malignancies including chronic lymphocytic leukemia. Recent data suggests a significant correlation between abnormal ratio of FLC and outcome. Therefore, we investigated the role of FLC in a large cohort of 135 patients and the correlation to immunofixation (IF) and flow cytometry. Abnormal FLC ratios were found in 78 patients (58%) whereas the IF was positive in only 32 cases (24%). In 55 cases the FLC ratio was positive while IF was negative and in only 9 cases IF was positive while the FLC ratio was normal. In 52 of 98 patients (53%) light chain restriction determined by flow cytometry was concordant with the monoclonal FLC whereas in 5 patients they did not agree. In 41 of 98 patients (42%) a normal ratio of FLC was observed while the immunophenotype was positive for lambda or kappa. Patients with an abnormal FLC ratio for lambda had a significantly shorter time to first therapy (TFT) than patients with an abnormal ratio for kappa FLC or with a normal FLC ratio (median TFT: 34 versus 76 versus 88 months, p for trend=0.039). Additionally, monoclonal FLC had a significantly shorter time to first treatment compared to polyclonal normal and abnormal FLC ratios (p for trend=0.0489). As expected, polyclonal sFLC correlated significantly with normal and abnormal serum-creatinine (p<0.0001). Future studies are warranted to elucidate the role of FLC as biomarkers of disease and as a prognostic factor for response.

Comprehensive Mutational Screening Of 5-Azacitidne Treated Myelodysplastic Syndrome (MDS) Patients Fails To Identify a Specific Mutational Profile Predicting Response To Therapy

Introduction5-azacitdine (aza) treatment in myelodysplastic syndrome (MDS) induces a response rate of 40-45% and prognostic factors for response and survival remain still largely unknown. Presence of mutant TET2 has been shown to predict better response to aza and the recently described French Azacitidine prognostic score segregates patients into 3 groups with varying median overall survival. Although a plethora of somatic mutations have been described in MDS, none has been consistently shown to be prognostically important in the context of response to hypomethylating agent(s). Patients and methodsTo identify the mutation signature associated with aza response, we undertook screening of 24 myeloid genes (splicing, epigenetic, transcription factors, STAG2, TP53) in 66 MDS patients treated with aza at our institution over a period of 2004-2012. Mutation analysis was done by deep (454 FLX) and Sanger sequencing. SNP-6 karyotyping was also performed in a subset to correlate with mutation status. Responses were assessed as per the international working group for MDS criteria.The median age was 67 years (range 36–87 years), median number of courses 7(range 2–42), 79% of patients belonged to int-2/high risk IPSS category. WHO category subtypes were; RA/RARS-2; RCMD-9; RAEB-39; s-AML (evolved from pre-existing MDS) -5, therapy related myeloid neoplasm (t-MDS/t-AML) -8 and CMML-3.IPSS cytogenetic subgroups were, good risk: 22, intermediate: 7, and poor risk: 37. One fourth of patients had received prior therapy, with only two receiving low dose cytarabine. Median time from diagnosis to aza treatment was 8.6 months. The overall response rate (ORR) to Aza was 47% (31/66) with complete response (CR) 17%, partial response (PR) 11%, marrow CR (mCR) 12% and stable disease with hematological improvement (SD-HI) 7%. ResultsCandidate mutations were seen in 82% (54/66) of patients, with the more than half harboring ≥2 mutations each. The most frequently (≥5 %) mutated genes being ASXL1 (29%), TP53 (23%), TET2 (14%), DNMT3A (12%), SRSF2 (12%), EZH2 (11%), NRAS (8%), U2AF1 (8%), IDH2 (8%), RUNX1 (8%), CCBL (6%) and FLT3-ITD (5%).On univariate analysis presence of EZH2 mutations predicted for a better ORR compared to wild type EZH2 (21% vs. 3%, p<0.04). TET2 mutations did not confer a better response (13% vs. 14%, p=0.1). None of other mutations predicted response. In multivariate logistic regression analysis, only shorter duration of disease (< than 8 months) predicted a better response (p=0.33,HR 0.29,CI 0.07-0.9).Patients with any mutation had a worse outcome compared to patients with no mutations (p=0.03, med OS 12.4 vs. 20.2 months). TP53 mutations were detected and quantified by high throughput sequencing in poor risk IPSS cytogenetic group (15/37) and were absent in patients with normal cytogenetics and isolated chromosome 7 abnormalities. Sequential samples were available in 9 patients and changes in clone sizes were correlative of treatment response, with 3 patients achieving cytogenetic response with concurrent reduction in clone size but the responses were transient. The TP53 mutation status correlated strongly with finding aberration of chromosome 17p by SNP array and positive p53 antibody staining on bone marrow trephine. On univariate analysis, TP53 mutations had an adverse impact on OS (P=0.0001, med OS 9.7 vs. 20.2 months).Age, IPSS cytogenetic risk group, WHO subtypes, overall response rate (ORR),progression to AML, TP53 mutation status and presence of EZH2 ,ASXLI,TET2,DNMT3A, SRSF2,NRAS mutations were used as co-variables in multivariate analysis.TP53 mutation status (HR=7.9(3.9-17.8), p=0.0001) and DNMT3A mutations (HR=2.5 (1.03-6.2), p=0.04) were established as independent prognostic variables influencing OS. Additionally, ORR to aza treatment imparts a better survival advantage (HR=0.3 (0.16-0.57),p=0.0001) ConclusionThis study shows that gene mutations are frequent in all cytogenetic subgroups of MDS. TET2 mutations did not predict response to aza contrary to published reports, which could be due to differences especially as low dose cytarabine was infrequently used in our cohort. TP53 mutations do not correlate with response rate but imparts a dismal prognosis. In conclusion, although we have screened comprehensively we do not identify a mutational profile predictive of response to azacitdine. Disclosures:No relevant conflicts of interest to declare.

Comment on Campana et al.: Radiolabelled somatostatin analogue treatment in gastroenteropancreatic neuroendocrine tumours: factors associated with response and suggestions for therapeutic sequence

Dear Sir, We read with great interest the recently published article by Campana et al. on outcome of peptide receptor radionuclide therapy (PRRT) and potential predictive factors [1]. This study included 69 patients regardless of whether Luor Y-based PRRT was applied. The authors concluded that stage of the disease (stage IV vs III), proliferation rate (G2 vs G1) and presence of previous transarterial chemoembolization (TACE) are significant factors for progression-free survival. Regarding the significance of the “tumour proliferation rate”, the authors stated in their discussion: “In general, it is well known that Ki-67 is a major prognostic factor for NETs. However, our data confirmed the role of tumour differentiation and Ki-67 as crucial therapeutic prognostic factors for response to PRRT in NETs as well.”Our group has previously evaluated this issue and the results have been published in the paper entitled “Impact of the Ki-67 proliferation index on response to peptide receptor radionuclide therapy” in the European Journal of Nuclear Medicine and Molecular Imaging in 2011 [2]. Unfortunately, this paper has not been cited by Campana et al. and is conspicuously missing in their discussion dealing with this topic. In our study, we specifically analysed the issue and were able to show that there was in fact no loss of response efficacy associated with higher proliferation indices in the G1–2 range, in particular not in NET with Ki-67 of 15–20 or 20 %. Our analysis was—in contrast to Campana et al. (n =63 patients with known Ki-67 index, either treated with Luor Y-based PRRT)—based on data of a uniformly treated cohort (n =81 patients receiving Lu-octreotate, all with characterized pretreatment proliferation rate). It is important to bring this paper to the reader’s attention as it provides a strong rationale not to preclude patients from PRRT because of proliferation indices in the high intermediate range (15–20 %). Another general comment on the study of Campana et al. is regarding analysis of predictive factors. It is reasonable to be more cautious in terms of validity of the multivariate analysis when applying such a large number of variables, where the number of patients is about 5 times the number of examined factors. The heterogeneity of the cohort not only of PRRT radiopharmaceuticals used (Y, Lu) but also stage of disease [n =15 patients (21.7 %) with stage III, i.e. with no distant metastases!] further weakens the analysis and might explain the discrepancy of results with previous reports on larger and more homogeneous cohorts regarding potential predictive factors [3, 4]. Thus, the discussion should be handled with particular care and conclusions should accordingly be attenuated. In summary, we like to point out that—as long as within the G1–2 range—increased Ki-67 indices should not serve as an argument against PRRTand call attention to the fact that this is supported by solid data, which may be referenced for any future multidisciplinary debates on this important issue.

Long-term follow-up of 163 consecutive patients treated with isolated limb perfusion for in-transit metastases of malignant melanoma

Purpose: The aim of the present study is to describe our experience with isolated limb perfusion (ILP) in the treatment of in-transit metastases of malignant melanoma and to determine prognostic factors for response, local progression, survival and toxicity. Materials and methods: A retrospective follow-up of all patients (n = 163) treated between January 1984 and December 2008 using data collected from individual patient records and the Swedish National Patient Register. Results: Clinical response was evaluable in 155 patients, 65% had a complete response (CR) and 20% had a partial response (PR). Local progression occurred in 63% of the patients after a median time of 16 months. Negative prognostic factors in univariate analyses were proximal location of the primary tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, proximal location of the primary tumour and no CR after ILP were significant prognostic factors. Median cancer-specific survival was 30 months, and negative prognostic factors in univariate analyses were male gender, positive lymph node status, systemic metastases, bulky tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, positive lymph node status, bulky tumour and no CR after ILP were significant prognostic factors. A majority (97%) of the patients had a Wieberdink grade II–III local toxicity. Four patients underwent limb amputation after a median of 19 months, none because of toxicity. Conclusion: We found that ILP is a safe method with a high response rate for the treatment of patients with in-transit metastases of malignant melanoma.

O-010 Prognostic factors of response to azacitidine (AZA) in low-risk MDS resistant to erythroid stimulating agents (ESA). The GFM Azaepo 08 study

Conclusions: Our data demonstrate that HSCs are disease-initiating cells in MDS. While MDS HSCs exhibit relatively few functional differences from their normal counterparts, committed myeloid progenitors in low-risk MDS exhibit numerous alterations including loss of GMPs, upregulation of CRT, and increased phagocytosis by macrophages, with increased expression of CD47 and decreased phagocytosis associated with disease progression. These findings are consistent with a model in which committed progenitors in MDS undergo molecular alterations that promote programmed cell removal, thereby resulting in the cytopenias that characterize MDS, but this mechanism does not appear to be critical for disease maintenance by HSCs.

Abstract 1954: Circulating microRNA-21 predicts the response to hypomethylating agents in patients with myelodysplastic syndromes.

Abstract Background: Although hypomethylating agents therapy have considerably improved the outcomes of patients with myelodysplastic syndromes (MDS), the discovery of sensitive non-invasive biomarkers that can facilitate the prediction of response to hypomethylating agents (HMA) and therapeutic outcomes are highly desirable to determine optimized strategies of epigenetic therapy for MDS. Circulating microRNAs have been evaluated as potential biomarkers for cancer diagnosis and prognosis prediction. Purpose: We evaluated the significance of miR-21 expression in serum as a biomarker for predicting response in MDS patients treated with HMA. Patients and methods: Serum miR-21 level was measured by quantitative real-time PCR in 58 MDS patients at diagnosis and 14 healthy controls. We analyzed the correlation between serum miR-21 level and clinical characteristics and response to HMA and survival. Results: We found that serum miR-21 level was significantly downregulated in patients with MDS than those in healthy controls (P&amp;lt;0.001). Moreover, miR-21 level was significantly lower in patients with response (CR, mCR, PR and SD with HI) to HMA compared to those without response (median, 0.9414±0.6349 vs. 1.1443±0.7707; P=0.041). Receiver-operator characteristic curve analysis indicated that serum miR-21 was useful in differentiating responder from non-responder with AUC of 0.648. At a cut-off value of 1.2613 for serum miR-21 level, the optimal sensitivity and specificity were 83.3% (95% CI: 68.6-93.3%) and 45.8% (95%CI: 25.5-67.1%), respectively. Patients, whose miR-21 level at diagnosis was higher than cutoff level, were defined as high miR-21 group (n=17) and the low miR-21 group representing the remaining 41 patients. We found that patients in high miR-21 grooup, compared with those in low miR-21 group, had a shorter median PFS (P=0.001). On multivariate analysis, Serum miR-21 level remained as a significant prognostic factor for response to HMA and PFS. Conclusion: In this study, we evaluated the levels of serum miR-21 in patients with MDS, and found that serum miR-21 level predicts response to HMA and PFS in MDS. Although this prognostic significance should be validated in an independent set of patients receiving HMA, serum miR-21 level is a promising biochemical marker for response prediction to HMT. Citation Format: Yoo Hong Min, Jae Yong Cho, Yundeok Kim, Yeo-Kyeoung Kim, Soo Jeong Kim, Jin Seok Kim, June-Won Cheong, Hyeuong Joon Kim. Circulating microRNA-21 predicts the response to hypomethylating agents in patients with myelodysplastic syndromes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1954. doi:10.1158/1538-7445.AM2013-1954

Developments in the Management of Advanced Non Small Cell Lung Cancer

Background: Overall survival (OS) and quality of life in patients with advanced non small cell lung cancer (NSCLC) remains to the day highly unsatisfactory. Better understanding of the mechanisms of oncogenesis resulted in the development of new drugs, which target a specific stage in tumor development. Additionally, optimal timing of chemotherapy administration has been readdressed with the introduction of maintenance treatment in clinical practice. The aim of this review is to briefly summarize the developments in first line treatment of NSCLC with small molecule tyrosine kinase inhibitors, the role of crizotinib and the current options in maintenance treatment. Methodology A search was performed in the PubMed database and in Clinical Trials.gov using the keywords erlotinib, gefitinib, crizotinib and maintenance treatment. Findings were reported in form of a narrative review. Conclusions: First line treatment with small molecule TKIs for NSCLC is both effective and feasible. EGFR mutation status remains the main prognostic factor of response. Pemetrexed and Erlotinib, currently approved for Maintenance Treatment in NSCLC, seem to benefit patients with advanced disease. Identification of suitable candidates for Maintenance Treatment, optimal timing and agent selection are issues that still remain largely unanswered. Early study results promise that addition of crizotinib to the treatment regimen of ALK positive NSLCL is likely to be beneficiary for a substantial number of patients.

Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation

AbstractBecause information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC transplants performed for AML in complete remission (CR) between 1999 and 2008, cumulative incidence of relapse was 32% ± 1%. Relapsed patients (263) were included into a detailed analysis of risk factors for overall survival (OS) and building of a prognostic score. CR was reinduced in 32%; remission duration after transplantation was the only prognostic factor for response (P = .003). Estimated 2-year OS from relapse was 14%, thereby resembling results of AML relapse after standard conditioning. Among variables available at the time of relapse, remission after HSCT > 5 months (hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.37-0.67, P < .001), bone marrow blasts less than 27% (HR = 0.53, 95% CI, 0.40-0.72, P < .001), and absence of acute GVHD after HSCT (HR = 0.67, 95% CI, 0.49-0.93, P = .017) were associated with better OS. Based on these factors, 3 prognostic groups could be discriminated, showing OS of 32% ± 7%, 19% ± 4%, and 4% ± 2% at 2 years (P < .0001). Long-term survival was achieved almost exclusively after successful induction of CR by cytoreductive therapy, followed either by donor lymphocyte infusion or second HSCT for consolidation.

Prognostic Factors of Response and Survival in CMML Patients Treated with Azacitidine (AZA)

Abstract 1726 Background:Treatment of CMML remains a clinical challenge, with no drug demonstrating clear clinical benefit. AZA yielded a survival benefit in higher risk MDS in a study that included few patients with CMML (AZA 001 trial, 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 numbers were small with heterogeneous risk factors. Methods:A cohort of CMML pts (according to WHO classification) treated with AZA in 3 programs (French AZA compassionate program, Cleveland Clinic Foundation and H. Lee Moffitt Cancer Center) were reviewed. All pts received AZA for at least one cycle (75 mg/m2/d during 7 days every 28 d). Response was evaluated according to IWG 2006 criteria in patients with WBC <13G/L, but also took into account “proliferative” features of CMML (including palpable splenomegaly [SM] and white blood cell count [WBC] in patients with WBC > 13G/l), in agreement with our previous experience (Wattel, Blood 1996; Braun, Blood 2011 online). Results:Between 2004 and 2009, 79 CMML pts received AZA. The median age was 70 y (range 33–85), M/F: 50/29. Median interval from diagnosis to treatment was <6 months in 30 pts, 6–12 months in 10 pts and > 12 months in 34 pts. At onset of AZA, median WBC, Hb level and platelet count were 11.4 G/l (range 7–122), 10 g/dl (range 6.3–15.2) and 59 G/l (range 9–1214), respectively. According to the WHO classification, 53% were CMML1 and 47% CMML2. Forty six percent of pts had WBC > 13 G/l and 32% had palpable SM (44% pts had neither of those features, 32% pts had one and 23% had both). Among pts with WBC<13G/l, IPSS was low or int 1 in 24% pts and high or int 2 in 30%. Prior to AZA, 48% pts received previous therapy, including growth factors in 13%, hydroxyurea in 18% and intensive chemotherapy in 17% patients. Karyotype was normal (57%), with chromosome 5/7 abn (14%), and with other cytogenetic changes (29%). The median number of cycles of AZA administered was 6 (range 1–40).Thirty-four pts (43%) responded including CR (16%), PR (1.5%), marrow CR (8%), hematological improvement (HI) (18%). Among 60 pts who received more than 4 cycles, 33 (55%) responded, including 13 (22%) who achieved CR. Patients who achieved response were significantly older (median 71 vs 66 years in non responders, p=0.0170).WBC count (p=0.4241), WBC >13 G/L (p=0.483), Hb level (p= 0.4529), platelet count (p= 0.1658), marrow blast % (p=0.4278), palpable SM (p= 0.319), cytogenetics (p=0.947), disease duration (p= 0.808), prior therapy (p= 0.277) and prior therapy excluding GF (p= 0.147) had no impact on response. Twenty-six patients progressed to AML after a median of 630 d (range 85–1165 d), including 12/34 of the responders (6 CR, 1 PR and 5 HI).The median overall survival (OS) from initiation of AZA (OS) was 654 d. In univariate analysis, prior therapy when ESA were excluded (p=0.0488), palpable SM (median 420 d vs 870 d, p= 0.0230), WBC>13 G/l (420 vs 775, p= 0.0412), presence of palpable SM and/ or WBC>13G/l (none: median 876d vs either: 750d vs both: 401d, p= 0.0054) (figure 1) IPSS in pts with WBC<13 G/l (1085d for low /int1 vs 682 for high/ int2, p= 0.0046), marrow blast >10 % (383d vs 682d, p=0.028) significantly influenced OS while Karyotype (p=0.4217), sex (p= 0.5174) and Hb level had no influence on OS. By multivariate analysis, only marrow blasts>10 % (HR=2.19 (1.13–4.2), p=0.02) and presence of proliferative features (WBC>13G/L and/or palpable SM) (HR= 2.08 (.94 −4.6),p= 0.06) had prognostic value for OS. Finally, using a landmark analysis performed at 3 mo, Patients who achieved a response had a significantly better OS compared to patients who failed to respond (median 889 d vs 569 d, p= 0.047). Conclusion:In this population of CMML patients with generally poor prognostic features, the response rates (ORR 43%) and overall survival (21 mo) with AZA treatment was similar to that previously reported in higher risk MDS. No significant predictive factors for response to AZA were identified, but marrow blast % and proliferative features (including increased WBC count and/or splenomegaly) were adverse prognostic factors for survival. [Display omitted] Disclosures:Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Celgene: Membership on an entity's Board of Directors or advisory committees. List:Celegene: Consultancy. Fenaux:Celgene: Membership on an entity's Board of Directors or advisory committees. Komrokji:Celgene: Research Funding, Speakers Bureau.

Genetic Variants of Interferon-Stimulated Genes and IL-28B as Host Prognostic Factors of Response to Combination Treatment for Chronic Hepatitis C

Chronic hepatitis C (CHC) is a worldwide health problem that is highly related to liver fibrosis, cirrhosis, and hepatocellular carcinoma. The achievement of response to the current standard of care-pegylated interferon plus ribavirin-has recently been described to be associated with single-nucleotide polymorphisms (SNPs) near the IL-28B gene. Additionally, baseline expression levels of genes involved in interferon (IFN)-stimulated genes (ISGs) have been found to be related to treatment outcome. In the present study, 285 patients were genotyped for 63 SNPs within genes of the IFN signaling pathway (IPGs) and ISGs. Two ISG polymorphisms-OASL rs12819210 (odds ratio (OR)=2.1, P=0.03) and IFIT1 rs304478 (OR=2.5, P=0.01)-were found to be independent predictive factors of sustained virological response (SVR) after adjusting for other clinical covariates. Furthermore, the predictive value of IL-28B SNP was notably improved by simultaneous genotyping of rs12819210 and rs304478, particularly in patients with the worst prognosis (viral genotype 1, area under the curve (AUC)=0.74). In conclusion, ISG SNPs could constitute a valuable tool for individualizing CHC therapy.

American Society of Clinical Oncology 2011 CNS tumors update

A number of important studies were presented at the CNS tumors section of the 2011 American Society of Clinical Oncology Annual Meeting. There was particular interest in RTOG 0525, a Phase III study of newly diagnosed glioblastoma treated with different schedules of temozolomide. Prognostic factors for response, survival and chemotherapy-related toxicity in primary CNS lymphoma from the German randomized Phase III trial in newly diagnosed primary CNS lymphoma were also presented.

P4.40 Enzyme Replacement Therapy and prognostic factors for response: An ongoing open-label cohort study in adults with Pompe Disease

Enzyme Replacement Therapy (ERT) for Pompe disease was approved for clinical use in 2006 based on the efficacy of alglucosidase alfa in classic infantile patients. More recently, treatment efficacy was demonstrated in adults. We evaluated the long-term effects of ERT and compared effects with the natural disease course. Furthermore prognostic factors for treatment response were identified. In this ongoing prospective study, we included 71 adults who were treated with 20mg/kg alglucosidase alfa every other week.

Prognostic factors for response and survival in primary central nervous system lymphoma (PCNSL) from a randomized phase III trial (G-PCNSL-SG-1).

2004 Background: The purpose of this study was to establish prognostic factors in newly diagnosed primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Methods: Four-hundred and eleven patients (median age 63 years, median Karnofsky performance status (KPS) 70%) enrolled in a German multicenter randomized phase III trial (G-PCNSL-SG-1) between May 2000 and May 2009 were analyzed using univariate and multivariate logistic regression analyses to identify prognostic factors for overall response (OR) and progression-free (PFS) and overall survival (OS). Patients were treated upfront with high-dose methotrexate (HDMTX) or HDMTX plus ifosfamide and were whole-brain irradiated thereafter if randomized to radiotherapy and treated with high-dose cytarabine (patients without complete remission) or just followed-up (patients with complete remission) if randomized to chemotherapy alone. Results: On multivariate analysis, female gender (p = 0.003), no corticosteroid medication at study entry (p = 0.003) and <2 tumor lesions (p = 0.009) were highly predictive for OR. Age (<60 vs. ≥60 years; p = 0.007) and KPS (≥70 vs. <70%; p <0.001) were strongly associated with OS. Further favorable prognostic factors (0.05 >p ≥0.01) on multivariate analysis were: HDMTX plus ifosfamide vs. HDMTX monotherapy (for OR), body mass index ≤25 (for OS), <2 tumor lesions (for PFS and OS), and KPS ≥70% (for PFS). Conclusions: This is the first study that established prognostic factors for OR and survival in PCNSL derived from a multicenter, prospective, randomized phase III trial. The data, especially the strong association of age and KPS with OS, should be taken into consideration in the design of future studies in PCNSL.

Analysis of factors predicting success of metformin and clomiphene treatment for women with infertility owing to PCOS-related ovulation dysfunction in a randomised controlled trial

Metformin has failed to gain wide acceptance as a first-line treatment option for women with anovulatory infertility related to polycystic ovary syndrome. This study aimed to ascertain factors that predict fertility success with treatment that included metformin compared to standard (non-metformin) treatment. Randomised trial data analysis by logistic regression of factors likely to have a differential influence on the likelihood of success of metformin versus non-metformin treatment amongst women with ovulation dysfunction related to polycystic ovary syndrome. metformin versus those receiving placebo and those with lower BMI who received metformin were more likely to become pregnant than their lower BMI counterparts who received placebo (P=0.039). The subpopulation of women with BMI≤32 kg/m(2) had no factors showing a significantly different impact on the chance of pregnancy for women treated with metformin versus those receiving clomiphene treatment or combination metformin/clomiphene treatment versus clomiphene treatment. There were no significantly different effects of free testosterone, fasting insulin, duration of infertility or ultrasound appearance of polycystic ovaries in any treatment groups. This study provides preliminary evidence that BMI may be an important prognostic factor in response to metformin for women with ovulation dysfunction related to polycystic ovary syndrome, suggesting that women with a lower BMI may respond better to metformin treatment versus placebo amongst women with BMI>32 kg/m(2) . Individual patient data meta-analysis of existing randomised trials would clarify this further and would assess whether other factors might predict better response to metformin versus standard treatments.

Prognostic factors for response to systemic treatments carried out in patients with advanced renal carcinoma.

369 Background: The analysis of predictive factors of response could help to select those patients with advanced renal cell carcinoma (RCC) who would be good candidates for systemic treatments Methods: The expression of several biomarkers was retrospectively analysed by immunohistochemistry (IHC), as well as 2 analytical variables: thrombocytosis and neutrophilia, in 135 patients with advanced RCC treated with cytokines (CK) and/or biological agents and was correlated to the response. Results: 67 patients were treated only with biological agents and 68 with CK (23 treated also with biological agents). Univariate statistical analysis: HIF-1alpha did not correlate significantly with the response to these drugs. The overexpression of ACIX was associated to a larger response (%) to biological agents such as sunitinib (65.9 vs. 16.7 p&lt;0.001) or sorafenib (61.9 vs 0 p=0.007), and CK (22.6 vs. 0 p=0.038). PTEN showed a predictive value for response (%) to sunitinib (70.8 vs. 34.1 with PTEN negative p=0.005). p21 was associated to a lower response (%) with sunitinib (35.9 vs. 65.4 with p=0.025). Thrombocytosis was not significantly associated with the response (%) to biological agents, although it was associated to CK (0 vs. 20 without thrombocytosis p=0.017). Neutrophilia correlated with a smaller response to biological agents (29.6 vs. 57.5 without neutrophilia, p=0.045), although it did not associate with a response to CK. In the multivariate analysis, overexpression of ACIX was an independent predictor of a larger response to biological agents and CK with an OR of 8,773 (p&lt;0.001). Conclusions: Our findings prove the usefulness of ACIX to select patients with advanced RCC candidates to receive systemic treatment. PTEN and p21 could be important in the prediction of response to sunitinib. Thrombocytosis and neutrophilia appear to relate to the response to CK and biological agents respectively. No significant financial relationships to disclose.

P214 Prognostic factors for response to neoadjuvant chemotherapy in patients with breast cancer

P214 Prognostic factors for response to neoadjuvant chemotherapy in patients with breast cancer

Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine

AbstractPrognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P = .009), bone marrow blasts > 15% (P = .004), and abnormal karyotype (P = .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P = .0003). Performance status ≥ 2, intermediate- and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency ≥ 4 units/8 weeks (all P < 10−4) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10−4). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P = .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10−4). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment.

A New MicroRNA Risk Model for Prediction of Clinical Outcome In Chronic Lymphocytic Leukemia

AbstractAbstract 3592 Introduction:Increasing experimental evidence supports the idea of aberrant microRNA (miRNA) expression in cancer pathogenesis, especially in chronic lymphocytic leukemia (CLL). Recently, aberrant expression of miR-29c and miR-223 has been associated with CLL outcome. Moreover, low expression of miR-34a in CLL is associated with p53 inactivation and also chemotherapy-refractory disease.Therefore, we investigated miR-29c, miR-223 and miR-34a expression in a large representative cohort of 110 CLL patients in order to assess the role of these miRNAs in risk prediction in B-CLL. Methods:Mononuclear cells of B-CLL were isolated from whole blood by centrifugation on a Ficoll/Hypaque gradient and cryopreserved in liquid nitrogen. MicroRNA was extracted from native liquid-nitrogen frozen cells using the QIAGEN miRNeasy® mini kit (Qiagen, Hilden, Germany). The relative expression of mature miRNAs was quantified using the TaqMan MicroRNA RT kit and TaqMan® MicroRNA Assays (Applied Biosystems, Foster City, California) on the ABI 7500 Real Time PCR System (Applied Biosystems, Foster City, California). RNU6B was used as internal control. The relative expression of each microRNA of interest to RNU6B was calculated using the formula miRNA of interest/RNU6B=2-deltaCt(miRNA-RNU6B). Result:The impact of the three miRNA expressions on treatment-free survival (TFS) and overall survival (OS) was assessed by performing “Receiver Operating Characteristics” (ROC) curve analysis. Patients with low miR-29c, miR-223 or miR-34a expression had a shorter TFS and OS than those patients with high expression:miR-29c: TFS 49 vs 91 months (p=0.081); OS 164 months vs not reached (p=0.093)miR-223: TFS 27 vs 84 months (p=0.035); OS 132 months vs not reached (p=0.001)miR-34a: TFS 46 vs 83 months (p=0.084); OS 132 months vs not reached (p=0.001)Furthermore, we investigated whether combining information on the expression of miRNAs could help refine the prognostic information provided by either of the three risk factors (RF) alone. Adding the number of risk factors this approach allowed for highly significant separation of our patient cohort into four subgroups, which differed significantly with regard to their clinical outcome.TFS: 0 RF 99 months; 1 RF 75 months; 2 RF 26 months; 3 RF 22 months (p=0.008)OS: 0 RF not reached; 1 RF not reached; 2 RF 164 months; 3 RF 132 months (p<0.0001)Moreover, in multivariate analysis the miRNA risk model was a significant independent prognostic factor (HR 1.3; 95%CI 1.0–1.8; p=0.04) next to the stage of Binet (HR 2.1; 95%CI 1.4–3.4; p=0.001) and ZAP-70 status (HR 3.0; 95%CI 1.5–5.9; p=0.002). Conclusion:Combined analysis of miR-29c, miR-223 and miR-34a expression in a risk model may help optimize currently available prognostic instruments. Future studies are warranted to elucidate the role of miRNAs as a prognostic factor for response and clinical outcome. Disclosures:No relevant conflicts of interest to declare.

A Prognostic Score for Overall Survival (OS) with Azacitidine (AZA) In Higher Risk MDS Based on 282 Patients (pts), and Validated In 175 Pts From the AZA 001 Trial

AbstractAbstract 3996 Background:AZA significantly improves OS in higher-risk MDS (including RAEB-t/AML) compared to conventional treatments (AZA 001 trial, Lancet Onc, 2009), but prognostic factors of response and OS to AZA remain largely unknown. We designed a prognostic score for OS in a cohort of AZA treated higher-risk MDS in a patient-named compassionate program (French ATU), and validated it in patients from the AZA 001 trial. Methods:Between Sept 2004 and Jan 2009, prior to AZA approval in Europe, IPSS int-2/high risk MDS (including RAEB-t) not previously treated with intensive chemotherapy (IC), allo SCT, or a hypomethylating agent were included in a compassionate program (ATU), and received AZA (planned schedule 75 mg/m2/d ×7 d every 28 d for ≥4 cycles). Independent prognostic factors of OS were individualized in a Cox model. A prognostic score was then developed based on those factors. After validation of the score as a continuous variable, pts were grouped in three distinct risk categories. We subsequently tried to validate this score in the 175 higher risk MDS pts treated with AZA at the same schedule in AZA 001 trial (4 of the 179 pts randomized to AZA in that trial did not start AZA). Results:The ATU cohort included 282 pts with de novo (74%) or therapy related (t) (26%) higher-risk MDS (IPSS int-2 in 54% high in 43%, at least int-2 in 2%). ECOG PS ≥2, RBC transfusion dependence ≥4 units/8 weeks and circulating blasts were present in 21%, 46% and 46% of pts respectively (resp). Cytogenetic risk was good, int, and poor in 31%, 17% and 47% (unknown in 5%). 10% pts had previously been treated with LD araC for their MDS. Multivariate analysis of survival retained PS ≥2 (HR= 2.0 [95% CI: 1.4–2.9]), RBC transfusion dependence ≥4 units/8 weeks (HR=1.9 [1.4-2.6]), presence of circulating blasts (HR=2.0 [1.5-2.7]), and IPSS cytogenetic risk (intermediate: HR=1.4 [0.8-2.3], poor: HR=3.0 [2.0-4.3]) as independent prognostic factors (all p<10-4). We designed a simple prognostic score attributing 1 and 2 points for intermediate and poor risk cytogenetics, resp, and 1 point for each other adverse prognostic factor. As a continuous variable, an increasing score was associated to poorer OS (HR=1.9 [1.6-2.1], p<10-4). Patients were grouped as “low risk” (score=0), intermediate risk (score=1-3) and high risk (score=4-5). Due to missing values, a prognostic group could be attributed to 269 of the 282 pts: 30 (11%), 191 (71%), and 48 (18%) pts were considered low, intermediate and high risk resp. With a median follow-up of 26 months, median OS were not reached, 15.0 and 6.1 months in patients with low, intermediate, and high risk score respectively (p<10-4).The validation cohort included 175 pts of the AZA-001 trial with higher-risk MDS. Apart from the presence of 5 (3%) int-1 pts in AZA-001 cohort (their removal did not affect conclusions), IPSS (int-2 in 42% high in 46%, at least int-2 in 9% vs 54%, 43%, 2% resp., p=0.15) was comparable to the ATU cohort, as well as RBC transfusion dependence ≥4 units/8 weeks (46 vs 45%, p=0.8), presence of circulating blasts (51 vs 45%, p=0.4), whereas all AZA-001 pts were de novo (vs 74% in the ATU cohort), had not been pretreated (vs 10% pretreated by LD AraC in the ATU cohort), had better PS (7% PS ≥2 vs 21% in the ATU cohort, p<10-4) and better cytogenetics (47%, 21% and 27% 5%, good, int, poor, unknown cytogenetics vs 31%, 17%, 47%, 5% resp., p<10-4). The score was validated as a continuous variable on OS (HR=1.4 [1.2-1.7], p=0.0005). Due to missing values, a prognostic group could be attributed to 166 (95%) of pts of the AZA 001 cohort: 27 (16%), 123 (74%), and 16 (10%) pts were classified in the low, intermediate and high risk respectively. Median follow-up was 21 months. Median OS were not reached, 21.4 and 14.3 months respectively in patients with low, intermediate, and high risk score (p=0.004). Conclusion:Our compassionate cohort scoring system based on conventional prognostic factors (ECOG PS, RBC transfusion requirement, circulating blasts and karyotype) was prognostic for survival. Additionally, it was successfully validated in a more selected cohort of higher-risk MDS from a prospective multicenter trial. Prognostic factors of outcome with AZA based on more refined biological studies (including gene methylation status) will probably emerge. In particular, we found in a more recent patient cohort (Itzykson, abstract also submitted to ASH 2010), that TET2 mutations may predict better response to AZA in higher risk MDS. [Display omitted] Disclosures:Beach:Celgene: Employment. Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding.