Articles de revues : « Variable interest consolidation FIN 46 »

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Callahan, Carolyn M., Rodney E. Smith et Angela Wheeler Spencer. « An Examination of the Cost of Capital Implications of FIN 46 ». Accounting Review 87, n^o 4 (1 juillet 2012) : 1105–34. http://dx.doi.org/10.2308/accr-10272.

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ABSTRACT This study examines whether the adoption in 2003 of FASB Interpretation No. 46/R (FIN 46), Consolidation of Variable Interest Entities—An Interpretation of ARB No. 51, changed the cost of capital for affected firms. Using comparative analysis on a broad sample of 11,719 firm-quarter observations for 1,389 firms during the period 1998 through 2005, we find evidence that FIN 46 significantly increased the cost of equity capital for firms with affected variable interest entities (VIEs), an increase of approximately 50 basis points relative to firms reporting no material effect from the standard. Further, firms consolidating these formerly off-balance sheet structures experienced the largest increase. Taken together, these results suggest that FIN 46 reduced the opportunity for firms to use off-balance sheet structures to artificially reduce their cost of capital, a matter of regulatory concern. Data Availability: All data are available from public sources.

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Buccisano, Francesco, Luca Maurillo, Alfonso Piciocchi, Maria Ilaria Del Principe, Chiara Sarlo, Mariagiovanna Cefalo, Concetta Ditto et al. « Age-Stratified Analysis Of The Prognostic Role Of Minimal Residual Disease Detection By Flow Cytometry, In Adult Patients With Acute Myeloid Leukemia ». Blood 122, n^o 21 (15 novembre 2013) : 2649. http://dx.doi.org/10.1182/blood.v122.21.2649.2649.

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Abstract Although the therapy of acute myeloid leukemia (AML) has remarkably improved over the last 2-3 decades, two thirds of young adults still die of their disease. In elderly adults, who represent the majority of patients with AML, the results are even more unsatisfactory with less than 10% of patients being long-term survivors. Based on this, age is universally recognized as a critical prognosticator affecting outcome and therefore treatment choice. In consecutive series of adult patients with de novo AML, we have repeatedly demonstrated the prognostic role of minimal residual disease (MRD) as detected by flow cytometry. In particular, we have found that a level of MRD ≥ 3.5x10e-4 residual leukemic cells (RLC) at the end of consolidation is associated with a relapse rate of 70-80%. In the present study we evaluated whether the prognostic impact of MRD assessment after consolidation remained unaltered even in age-stratified (< 60 and > 60 years) populations of adult patients with de novo AML. To this end, we analyzed 149 young (median age 46, range 18-60) and 61 elderly adults (median age 67, range 61-78). All patients under study achieved complete remission after an induction therapy of the EORTC/GIMEMA protocols AML10, LAM99P and AML12 (for patients < 60 years) or AML13, AML15A and AML17 (for patients > 60 years). The two cohorts were well balanced in terms of frequency of FLT3-ITD and NPM1 mutated cases. A lower frequency of favorable-risk karyotypes was observed in elderly versus young patients (4% vs 19%, p=0.024). Of 149 younger patients, 105 (70%) underwent stem cell transplantation (SCT) (45 allogeneic, 60 autologous) as compared to 7 (11%) in the older age group (1 allogeneic, 6 autologous), (p=<0.0001). The frequency of MRD negative measurements was lower among elderly patients as compared to the younger ones [7/61 (11%) vs 42/146 (28%), p=0.009]. The median value of MRD after induction was 2.9x10e-3 RLC (range 0-170) and 3.1x10e-3 RLC (range 0-220) in younger and older patients (p=NS), respectively. Conversely, post-consolidation MRD levels were significantly lower in the younger cohort (1.7x10e-3 RLC, range 0-360) as compared to the older one (3.3 x10e-3 RLC, range 0-72), (p=0.018). In both age groups, disease-free survival (DFS) (Fig. 1) and cumulative incidence of relapse (CIR) were significantly longer and lower for patients who achieved MRD negativity at the post-consolidation time-point (p=0.0003 and <0.0001, respectively). In multivariate analysis, MRD at the post-consolidation time-point (p=0.0013) and karyotype (favorable vs adverse, p=0.0073; intermediate vs adverse, p=0.06) confirmed an independent prognostic role affecting DFS. Even SCT procedure (both autologous or allogeneic), analyzed as a time-dependent covariate, was significantly associated to DFS (p<0.001). Age did not score as a significant variable in any prognostic model. In conclusion, elderly adults with AML infrequently become flow-MRD negative after consolidation therapy (11% vs 29%, p=0.008), likely due to a less intensive approach. However, those who succeed to enter MRD negativity have significantly superior DFS and CIR – comparable to the ones of young patients - that than those who remain positive.Figure 1Disease free survival stratified according to age and MRD status.Figure 1. Disease free survival stratified according to age and MRD status. Disclosures: No relevant conflicts of interest to declare.

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Chasteen, Lanny G. « Teaching variable interest entities under FIN 46 : Untangling risks, expected losses, and expected residual returns ». Journal of Accounting Education 23, n^o 1 (janvier 2005) : 47–66. http://dx.doi.org/10.1016/j.jaccedu.2005.02.001.

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Schwab, Claire, Rebecca Andrews, Lucy Chilton, Alannah Elliott, Stacey Richardson, Sarra L. Ryan, Amy Logan et al. « SSBP2-CSF1R Is a Recurrent Fusion in B-Other Acute Lymphoblastic Leukaemia with Variable Clinical Outcome ». Blood 124, n^o 21 (6 décembre 2014) : 3773. http://dx.doi.org/10.1182/blood.v124.21.3773.3773.

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Abstract BCR-ABL1-like acute lymphoblastic leukaemia (ALL) is a subgroup of B cell precursor (BCP) ALL, which has a similar gene expression profile to BCR-ABL1 positive ALL and shares the same high risk of relapse. BCR-ABL1-like ALL is genetically heterogeneous and no single abnormality defines them. However a number of novel fusion genes have been reported in this subgroup, which involve the kinase genes: PDGFRB, CSF1R, ABL1, ABL2 and JAK2. Studies have shown that patients with these fusions may also respond to tyrosine kinase inhibitors (TKI), such as imatinib. Here we present a subset of patients with the SSBP2-CSF1R fusion, including a patient treated with imatinib after relapse. Five patients with BCP-ALL were identified with cytogenetically visible abnormalities of chromosome 5, which resulted in fusion of the SSBP2 at 5q14 to CSF1R at 5q33. Three patients showed balanced translocations, t(5;5)(q14;q33) and 2 showed duplication of the long arm of chromosome 5, dup(5)(q14q33). FISH analysis using in-house dual colour break-apart probes confirmed rearrangement of the CSF1R and SSBP2 genes in 4 patients. In the two cases showing dup(5)(q14q32) the duplication was confirmed by single nucleotide polymorphism (SNP) array analysis with the breakpoints occurring within SSBP2 and CSF1R. Paired end sequencing in 3 cases confirmed that the breakpoints within SSBP2 and CSF1R with the predicted transcriptional consequence being an in-frame fusion of SSBP2 exon 5 or 6 to CSF1Rexon 12. Genome wide SNP array analysis was performed in 4 cases, which revealed few copy number abnormalities (CNA) at diagnosis, with less than 5 CNA per patient. The only recurrent CNA was loss of IKZF1, seen in 2 patients; one had an intragenic deletion of exons 4-7 and the other a large deletion of approximately 22.5 Mb, spanning 7p11 to 7p14.2 and including biallelic loss of IKZF1exons 2-3. The clinical and demographic data for the five patients are shown in Table 1. Complete remission (CR) was achieved in all cases. Two patients, who were <10 years at diagnosis and received standard chemotherapy, have continued in CR1 for >10 years. The oldest patient was a 40 year old female who died due to graft versus host disease following a bone marrow transplant. Patients 4 and 5 were treated as high risk due to age, high WCC (>50 x109/L) and minimal residual disease (MRD) risk. Despite receiving intensive therapy, both patients suffered relapses. Patient 4, who relapsed while receiving consolidation therapy, failed to achieve CR2 and subsequently died. Patient 5 suffered an isolated bone marrow relapse one month after the end of treatment. She was treated according to the ALLR3 trial high risk arm and achieved CR2 and MRD negativity by day 35. The detection of the SSBP2-CSF1R fusion prompted the addition of imatinib (400 mg/d) to her regimen with the intention of maintaining remission until unrelated donor stem cell transplant. Unfortunately the patient died 11 weeks after relapse from infection (E. coli septicaemia). Although these cases were identified by cytogenetics, unbiased screening of a single childhood trial, UKALL2003 was carried out. Among 276 BCP-ALL patients without any of the established cytogenetic changes, a single case (Patient 4) with the SSBP2-CSF1Rfusion was identified. This equates to less than 0.1% of childhood BCP-ALL. The incidence and outcome in adult BCP-ALL remains to be determined. This study highlights the rarity and variable outcome for paediatric patients with SSBP2-CSF1R fusions. Two young children treated as low risk achieved long-term event free survival, however 2 older children classified as high risk suffered early relapses. It is possible that children with ALL who are SSBP2-CSF1Rpositive may benefit from the incorporation of TKI into their treatment regime in the early stages of their disease. Given the rarity of this abnormality, it may not be necessary to screen all children, however those with refractory or high risk ALL should be investigated for lesions potentially responsive to TKI. Table 1 Patient no. Age Sex Trial WCC(x109/L) Karyotype Follow up 1 2 M ALL97 50.3 46,XY,t(5;5)(q14q33) CR1 >10yrs 2 4 F ALL97 18.2 47,XX,t(5;5)(q14;q33),+21 CR1 >10yrs 3 40 F UKALLXII 12.1 Failed. arr [hg19] 5q14q33(80721553-149443298)x3 Remission death 4 10 M UKALL2003 301.8 46,XY,t(5;5)(q14;q33)/46,XY,idem,t(3;20)(p21;q13) Relapsed and died 5 11 F Non-trial 8 46,XX,dup(5)(q14q33)† Relapsed and died in CR2 † karyotype at relapse Disclosures No relevant conflicts of interest to declare.

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Hoang, Thuyvan, Wei Qiao, Jorge E. Cortes, Keyur Patel, Farhad Ravandi, Tapan M. Kadia, Mark Brandt, Raja Luthra, Hagop M. Kantarjian et Gautam Borthakur. « Quantitative Assessment of Translocation Transcript Ratio Predicts for Relapse Free Survival Among Patients with Core Binding Factor Acute Myeloid Leukemia ». Blood 124, n^o 21 (6 décembre 2014) : 2354. http://dx.doi.org/10.1182/blood.v124.21.2354.2354.

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Abstract Presence of unique translocation events allows us to monitor minimal residual disease by quantitative polymerase chain reaction (qPCR) in patients with core binding factor acute myeloid leukemia (CBF-AML) that includes Inversion(16), t(16;16) and t (8;21) cytogenetic abnormalities. Fludarabine based regimens; Fludarabine, cytarabine, G-CSF and gemtuzumab ozogamicin (FLAG-GO) and FLAG, idarubicin (FLAG-Ida) have been two consecutive regimens used as front-line therapy for all new patients with CBF-AML presenting to MD Anderson Cancer Center since 2007. MRD has been monitored by baseline and periodic qPCR studies from bone marrow samples during induction/consolidation and follow up. Based on recent literature we investigated whether time to achievement of lowest qPCR value or the lowest qPCR value are important to predict for relapse free survival (RFS) in a multi-variate analysis. Between 2007 and early 2014, 89 patients (pts) have achieved remission with frontline induction regimens; FLAG-GO=41 (46%) and FLAG-Ida=48 pts (54%); 44 patients with Inv (16) and 45 pts with t(8;21). Median presenting WBC count is 12.5x 106/L (range 1.9-97.2) and median qPCR ratio with ABL1 as control at presentation is >100. Median lowest qPCR following induction/consolidation is 0 (range 0-15.9) and is the same for inv (16) and t(8;21) (p=0.14). The median lowest qPCR value by regimen is 0 for FLAG-GO and the same for FLAG-Ida is 0.01 (p=0.003). RFS with a median follow up of more than 3 years is 80% and is not different among regimens (p=0.5). Because of infrequency of events, the analysis was mostly done using both cytogenetic groups and both regimens together. Median time to lowest qPCR was 7 months for both cytogenetic subgroups as well as for both FLAG-GO and FLAG-Ida regimens (range 1-28 months). In a univariate analysis that included age, log WBC and platelet counts, cytogenetics, regimen, time to lowest qPCR value and the log lowest qPCR value as variables; log lowest qPCR is the only variable significantly predicting for RFS (p<0.01) while time to lowest qPCR is not (p=0.7). Conclusion: RFS remains high among patients treated with FLAG-GO or FLAG-Ida and lowest qPCR value rather than the time to achieve lowest qPCR. Disclosures No relevant conflicts of interest to declare.

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Gray, James X., Lyle McMillen, Russell Saal, Steven Lane, Peter Mollee, Robert Bird, Devinder Gill et Paula Marlton. « WT1 Expression Levels at Diagnosis and as a Marker of Minimal Residual Disease (MRD) in Patients with Acute Myeloid Leukaemia (AML). » Blood 114, n^o 22 (20 novembre 2009) : 2639. http://dx.doi.org/10.1182/blood.v114.22.2639.2639.

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Abstract Abstract 2639 Poster Board II-615 Background.- As wt1 expression is elevated in the majority (80%) of acute myeloid leukemias at diagnosis and relapse, a validated wt1 assay would be a powerful adjunctive tool for evaluation and monitoring of patients during their treatment. Monitoring of disease status with wt1 is applicable to more AML patients in a single assay than any other leukemic marker and includes patients that are cytogenetically normal and may not otherwise be amenable to molecular MRD evaluation. We aimed to analyse wt1 expression in the peripheral blood and bone marrow of patients with de novo AML, when measured at diagnosis, post-induction and post-consolidation; and to correlate these wt1 expression levels with patient characteristics and outcome. Methods- This is a prospective, longitudinal study in which the levels of wt1 expression from 99 patients with de novo AML are measured from bone marrow (59 patients) and peripheral blood (94 patients) specimens at the time of diagnosis and at various time-points along their treatment and clinical courses. The specimens were prospectively stored in the PwC Australasian Leukaemia and Lymphoma Group (ALLG) Tissue Bank. Samples analysed included: 59 bone marrow (bm-wt1) and 94 peripheral blood (pb-wt1) at diagnosis; 54 bm-wt1 and 57 pb-wt1 post-induction; and 46 bm-wt1 and 41 pb-wt1 post-consolidation. 90 of the 99 patients were treated with standard induction chemotherapy on a variety of protocols. RNA was extracted from 107 leukocytes purified from blood and bone marrow using TRIzol® (Invitrogen) extraction. Reverse transcription was performed using Superscript ® (Invitrogen) and RQ-PCR was performed using multiplexed 5' nuclease assay with Black Hole Quencher labelled probes according to published methods. Copy number of wt1 was normalised to 104 copies of ABL. Baseline patient characteristics were correlated with baseline wt1 expression levels and the impact of baseline and post-treatment wt1 expression on leukemia-free survival (LFS) was assessed. Results- 99 AML patients were studied: median age 55years, 53% male. Cytogenetic prognostic groups (SWOG) were favourable – 12%, intermediate – 59% and poor – 29%. 90 patients were treated with curative intent and 83% achieved CR, 6% had refractory disease and 11% died during induction. With a median follow-up of 33 months, the median LFS was 12 months and median OS was 24 months. Median pb-wt1 levels at diagnosis were 5122 (range, 1 to 36125) and varied significantly according to: cytogenetic risk group (good risk 12745, intermediate risk 2632, poor risk 4554 (P = 0.009)) and marrow blast percentage (P = 0.02). Diagnostic bm-wt1 showed similar correlations with baseline parameters, but did not reach statistical significance. Median pb-wt1 at relapse was 3781. One of 21 relapsed patients with elevated pb-wt1 expression at diagnosis did not express wt1 at relapse. In a multivariate Cox regression analysis model including age and cytogenetic risk-group, increased expression of wt1 from peripheral blood at diagnosis is predictive of decreased LFS (P=0.04). This correlation was not seen with wt1 measured from bone marrow aspirates. The wt1 expression levels were reduced following induction chemotherapy with a median 2.6 log reduction (range, 0 to 4.2) seen in marrow aspirate and 3.2 log reduction (range, 0 to 4.3) seen in peripheral blood. There was a trend for lower post-induction peripheral blood wt1 to correlate with better LFS when measured as a continuous variable (P=0.067) or undetected vs detected (P=0.051). Lower post-consolidation pb-wt1 significantly correlated with better LFS when measured as a continuous variable (P=0.002) or undetected vs detected (P=0.02) and continued to be significant in multivariate analysis. Bone marrow aspirate wt1 levels post-induction or post-consolidation did not correlate with LFS. Conclusion- This study demonstrates a correlation between wt1 expression levels and known risk factors for early relapse. In the MRD setting, detectable wt1 levels in peripheral blood post-induction and post-consolidation predicted very poor leukaemia free survival. Analysis is ongoing to validate these findings in a uniformly treated cohort of patients enrolled on the current ALLG clinical trial. Disclosures: No relevant conflicts of interest to declare.

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Rubenstein, James L., Eric D. Hsi, Jeffrey L. Johnson, Sin-Ho Jung, Barbara Grant, Bruce D. Cheson et Lawrence D. Kaplan. « BCL6 Expression and Treatment Delay Correlate with Adverse Outcome in Newly Diagnosed Primary CNS Lymphoma : Final Report of CALGB 50202 (Alliance) ». Blood 120, n^o 21 (16 novembre 2012) : 301. http://dx.doi.org/10.1182/blood.v120.21.301.301.

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Abstract Abstract 301 Background: While whole brain radiotherapy (WBRT) has long been considered the standard consolidative therapy in primary CNS lymphoma (PCNSL), concerns regarding irreversible neurocognitive effects of brain irradiation have prompted development of dose-intensive induction and consolidative chemotherapeutic approaches, with the aim to eliminate brain irradiation. We present the updated results of the first Phase II multicenter trial, conducted by a major cooperative group within the United States, to evaluate an intensive chemotherapy-alone strategy in newly diagnosed patients with PCNSL. Methods: Induction chemotherapy consisted of methotrexate (MTX), temozolomide, rituximab (MT-R) with HD-MTX (8 gm/m2) administered every 2 weeks × 8, weekly rituximab × 6 and temozolomide (150 mg/m2) starting day +7 and continued monthly × 5. Patients who achieved a CR received intensive consolidation cytarabine 2 gm/m2 BID on days 1–4 with etoposide 40 mg/kg over 96 h (EA). Assessment of BCL6 and MYC expression by lymphoma cells was performed by immunohistochemical analysis of diagnostic specimens and scored (10% increments) by a pathologist who was blinded to clinical outcome. Results: 44 newly diagnosed, immunocompetent patients with PCNSL were treated at 12 CALGB centers between 2005 and 2009. Patient characteristics were as follows: median age was 61 yr (range 12–76), median ECOG PS was 1, 58% were IELSG risk group 2–3. 98% of tumors were large B-cell lymphoma. 66% of patients exhibited CR to induction MT-R. With median overall follow-up of 5.3 years, 21 out of 46 patients exhibited disease progression and 17 have died. There was one treatment-related death (sepsis) during consolidation. There has been no evidence for significant treatment-related neurotoxicity. The median progression-free survival (PFS) is 4.0 years and estimated PFS rates with 95% confidence limits at 1, 2, 3 and 4 years are 0.66 (0.50, 0.76), 0.59 (0.43, 0.72), 0.52 (0.36, 0.64) and 0.47 (0.32, 0.61). The probability of 2-year PFS for patients who completed the entire regimen is 0.69 (0.47, 0.94). The estimated overall survival (OS) rate with 95% confidence limits at 4 years is 0.65 (0.49,0.77). Remarkably, event-free survival (EFS) was similar in patients older and younger than 60 (p< 0.47). While ECOG PS>1 and high IELSG score showed a trend toward inferior EFS, the most significant clinical prognostic variable was treatment delay: those patients who started remission induction therapy more than 30 days after diagnosis exhibited shorter EFS than patients who received MT-R within a month (2-sided p-value = 0.05). There was no relationship between treatment delay and IELSG prognostic score. While high MYC expression (>50% lymphoma nuclei) was detected in 54% of cases, MYC was not prognostic. By contrast, high BCL6 expression (≥30% of lymphoma nuclei) was detected in 59% of cases and correlated as a continuous variable with inferior progression-free survival, event-free survival and overall survival. The 2-sided p-values for these models were p=0.045, p=0.019 and p=0.045 (log-rank test). Conclusions: CALGB 50202 (Alliance) demonstrates that induction MT-R followed by EA consolidation is feasible in the multicenter setting and yields rates of PFS and OS in newly diagnosed PCNSL patients that are at least comparable to combined modality treatment involving reduced dose whole brain irradiation. The MT-R-EA regimen is well-tolerated in patients age >60 and has similar efficacy in this population as in younger patients. Based upon these encouraging results, a successor, intergroup, randomized phase II trial, CALGB 51101 (Alliance) has been activated that compares dose-intensive consolidation (EA) with myeloablative chemotherapy and autologous stem cell transplant in this first randomized trial in PCNSL in which neither arm involves WBRT. Our observations regarding the association of treatment delay with adverse prognosis suggest that prompt initiation of therapy for PCNSL patients may translate into improved outcomes. In this first prospective analysis of molecular biomarkers in PCNSL in the setting of a clinical trial, high BCL6 expression was found to correlate with inferior outcome. This observation raises the possibility that in future studies BCL6 could be used as a biomarker in risk-adapted therapy and supports the investigation of BCL6 antagonists in the treatment of this disease. Supported by LLS and by NCI CA13908301. Disclosures: No relevant conflicts of interest to declare.

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Blau, Olga, Rimma Berenstein, Annette Sindram, Eckhard Thiel et Igor Wolfgang Blau. « FLT3-ITD Mutations in AML : Structural and Numerical Variation of Mutations and Identification of Subgroup with Poor Prognosis ». Blood 118, n^o 21 (18 novembre 2011) : 4868. http://dx.doi.org/10.1182/blood.v118.21.4868.4868.

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Abstract Abstract 4868 FLT3-ITD occurs with a frequency of 35%–45% in normal karyotype AML and has an adverse impact on prognosis. FLT3-ITD mutations are very variable in length and position of the tandem duplication. We have analyzed 211 AML patients with a median age of 54 years (range, 17–75). For all patients, intensive double-induction and consolidation therapy were intended. Patients with a matched related (MRD) or unrelated donor (MUD) were allocated to allogeneic stem cell transplantation (alloSCT). To investigate ITD insertion site and length, as well as their clinical impact in AML patients, we have performed sequencing analysis in diagnostic samples from 46 FT3- ITD–mutated patients. In 39 (87%) patients a single sequence was found, 6 patients displayed 2 and more different mutations. The median size of the inserted sequences was 63 nucleotides (range, 21–203 nucleotides). ITD integration sites were categorized according to functional regions of the FLT3 receptor: juxtamembrane domain (JMD), n =29 (JMD switch motif, n=3; JMD zipper motif, n=20; and JMD hinge region, n=6) and beta1-sheet of the tyrosine kinase domain-1 (TKD1), n=17. In the majority of the cases insertion sites were localized in JMD between amino acid (AA) 593 and 609 (n=20; 43%) and in TKD1 between AAs 610 and 615 (n=17; 37%). Integration site was strongly correlated with the ITD size (p=0.001) and with white blood cells (WBC) count (p=0.05). The prognostic significance of FLT3-ITD size is discussed controversial. Several studies reported conflicting results. We have found that CR durations was significant better (p=0.05) in patients with bigger ITD size, and there were no statistical differences in OS and DFS. There was no significant association between the number of mutations and OS or DFS. Presence of the any type of mutations was more common in M5 (16 of 54, 29%, P 0.01). It was associated with normal karyotype (72% vs 43%), p=0,0001; higher white blood cells (WBC) count (98×109/l vs 21×109/l), p=0,0001; higher BM blasts (85% vs 71%, p=0,0001), de novo AML (91% vs 69%), p=0,0001); and inferior OS (p=0,008) and DFS (p=0,01), when we excluded AML M3 patients. The prevalence of ITD allele on the DNA level was heterogeneous. Based on quantitative analysis, the mutant/wild-type (wt) ratio ranged from 0,1 to 11,5. Patients with a mutant/wt ratio above 0,3 had significantly shorter CR duration (p=0,02), OS (p=0,03), and DFS (p=0,01). Taken together, our data confirm that FLT3 mutation represent a common aberration in adult AML and associated with inferior outcome. A high mutant/wt ratio appears to have a major impact on the prognostic relevance. Disclosures: No relevant conflicts of interest to declare.

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García-Noblejas, Ana, Eulogio Conde, Alejandro Martín, María Jesús Vidal, Rafael Rojas, Carlos Grande, María José Ramirez et al. « Autologous Stem Cell Transplantation in Patients with Mantle Cell Lymphoma : A Retrospective Study of the Geltamo Group (1994-2011) ». Blood 124, n^o 21 (6 décembre 2014) : 3980. http://dx.doi.org/10.1182/blood.v124.21.3980.3980.

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Abstract INTRODUCTION Autologous stem cell transplantation (ASCT) is one of the current treatment options for first-line treatment of mantle cell lymphoma (MCL) in young and fit patients in first complete response (CR). Nevertheless its role in less than CR, after intensive chemotherapy schemas or as consolidation after salvage regimens has not been established. AIM To analyze the impact of patient and treatment characteristics on outcome of MCL patients treated with ASCT. METHODS Retrospective analysis of MCL patients treated with ASCT and registered in the GELTAMO database from 1994 to 2011. An outcome up-date was performed on December 2013. The study was approved by local ethical committees. Statistical analysis was performed using SPSS 15.0. RESULTS Two hundred and forty eight patients were registered from the GELTAMO database. Patients’characteristics : median age was 55 years old (range 21-70 y), 70% male. One hundred and fifty eight patients (68%) were transplanted in CR, 125 were in first CR (79% of all CR) and 33 in second or third CR (21%). Fifty two patients (22%) were transplanted in first partial response and 15 (6%) with chemosensitivity disease after relapse. Only 8 patients (3%) were transplanted with refractory disease. Response : forty-eight out of 75 patients (64%) without CR at ASCT converted to CR after transplant. Survival: Sixteen percent of patients were lost to follow-up one year after transplantation. Median follow-up for alive patients was 47 months (range 0-245 months). Progression free survival for patients transplanted in first CR was 45 months (CI95%: 33-56 months), for patients transplanted in first partial response (PR) was 28 months (CI95%: 15-21months) and for patients transplanted in other response was 19 months (CI95%: 12-26 months). In the whole series, median overall survival (OS) from transplantation was 69 months (CI95% 51-87 months) and for those patients transplanted in first CR was 98 months (CI95% 67-130 months). When patients without CR before transplant are analyzed separately, those who achieved CR after transplantation have better PFS (38 vs 10 months, p<0.001) and OS (74 vs 16 months, p<0.001) than others. Treatment related mortality was 4%. We analyzed the variables that could be associated with PFS and OS. We considered age (≤60 vs >60), ECOG (<2, ≥2), IPI (<2, ≥2), status at transplant (1st CR vs others), conditioning with TBI and HDAC in first line treatment. In univariate analysis, ECOG (p=0.04) and status at transplant (p=0.01) were the variables associated with PFS. For OS, the same variables resulted significant (p<0.001 and p=0.07, respectively) and also, HDAC emerged as significant variable associated with outcome. (p=0.05). In multivariate analysis, ECOG and status at transplant remained as independent prognostic factors for PFS while ECOG and HDAC in first line had impact for OS, see Table 1. Table 1. Variables identified as independent prognostic factors for PFS and OS in multivariate analysis. PFS OS p RR (95% CI) p RR ECOG 0.01 3.6 (1.3-9.9) 0.04 4.5 (1.6-12.5) Status at trasplant 0.03 1.4 (1-2) 0.09 (ns) ---- HDAC at 1st line 0.7 (ns) ---- 0.014 0.5 (0.3-0.8) Afterwards, a survival analysis for PFS and OS was performed according to have received high dose AraC (HDAC) in first line treatment or not and disease status (DS) before ASCT (Table 2). Table 2. Survival analysis according to have received HDAC in 1st line treatment and disease status (DS) before ASCT DS before ASCT N Firts line treatment N PFS (CI95%)(Kaplan Meier) p OS (CI95%)(Kaplan Meier) p 1st CR 125 No HDAC 52 37 (22-51) 0.13 64 (37-91) 0.01 HDAC 72 56 (33-78) No reached 1st PR 52 No HDAC 35 33 (3-63) 0.59 61 (0-126) 0.9 HDAC 17 27 (18-37) 69 (46-92) ≠1st CR/PR 51 No HDAC 46 20 (13-27) 0.16 35 (5-66) 0.9 HDAC 5 11 (7-16) No reached CONCLUSION This retrospective study reproduces previous results published about the role of ASCT in MCL: ASCT consolidation in first CR induces high survival rates with a median PFS of 45 months and median OS of 98 months. Patients without CR after ASCT had a significant inferior outcome. ECOG < 2 and status at transplantation are crucial for PFS and first line treatment with AraC improves significantly OS, particularly in patients with first CR. Disclosures No relevant conflicts of interest to declare.

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Robinson, Stephen, Christopher P. Fox, Rachel M. Pearce, Julia Perry, Keiren Kirkland, Charles F. Craddock, Nigel H. Russell et al. « BEAM-Campath Allogeneic Stem Cell Transplantation for Aggressive Non-Hodgkin's Lymphomas. An Analysis of Outcomes From the BSBMT ». Blood 120, n^o 21 (16 novembre 2012) : 2039. http://dx.doi.org/10.1182/blood.v120.21.2039.2039.

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Abstract Abstract 2039 Introduction. The role of allogeneic stem cell transplantation in the management of aggressive non-Hodgkin's lymphoma (NHL) remains to be established. Autologous stem cell transplantation (SCT) remains the standard salvage therapy for patients with diffuse large B cell lymphoma failing first line therapy although patients relapsing early after Rituximab based immunochemotherapy have a poor outcome. For patients with aggressive T cell lymphomas the role of consolidation or salvage transplant strategies also remains controversial. Reduced intensity allogeneic transplants have been employed in these diseases with variable success. In the United Kingdom the more intensive BEAM conditioning regimen has been employed prior to allogeneic stem cell transplantation in lymphoproliferative diseases. We report here the outcome of BEAM-CAMPATH conditioning prior to allogeneic stem cell transplantation for aggressive NHL as reported to the British Bone Marrow Registry. Methods. We retrospectively identified all patients reported to the BSBMT registry as having undergone an allogeneic stem cell transplant following BEAM-CAMPATH conditioning for aggressive non-Hodgkin's lymphomas. All patients received conditioning with BEAM (BCNU 300mg/m2, etoposide 800mg/m2, cytarabine 1600mg/m2, melphalan 140mg/m2) and CAMPATH-1H 10mg days -6 to -2. Cyclosporin A was administered for 90 days post transplant. Six transplant centres contributed data to this study. Results. 46 patients (27 male, 19 female) with a median age of 45 (range 17–59) at diagnosis with DLBCL (29), Burkitt's lymphoma (1) or T cell lymphoma (PTCL NOS 14, anaplastic large cell lymphoma 3, angioimmunoblastic lymphoma 1) were identified. 37 patients had stage III/IV disease at diagnosis and 56% of patients had a high or high-intermediate International Prognostic Score. They had received a median of 3 lines of prior therapy (range 1–5), 11 of 29 patients with B cell lymphomas had received Rituximab prior to transplant and 4 patients had received a prior autologous stem cell transplant. The median time from diagnosis to transplant was 11 months (range 3 months–13 years) and 22 patients had received the transplant in first response. At transplant 34 patients had chemosenstive disease and 11 patients had chemorefractory disease. Transplants from 32 siblings and 14 volunteer unrelated donors were performed using peripheral blood stem cells in 42 patients. 3 patients received a mismatched transplant. The Performance Status (PS) at transplant was good (KPS>80) in 40 of 46 patients. All patients engrafted with a median time to neutrophil recovery of 14 days (range 11–27). At last follow up 20 patients are alive with 17 in complete remission. 5 patients have died from non-relapse causes (infection 3, GVHD 1, respiratory failure 1) and 21 died following relapse of lymphoma. Acute GVHD grades II-IV developed in 7 patients and chronic GVHD in 13 (7 limited, 6 extensive) of 37 patients surviving beyond 100 days. The cumulative incidence (CI) of non-relapse mortality (NRM) was 7% at 100 days and 11% at 3 and 5 years post transplant. NRM was significantly worse for those with a poor PS, use of a VUD, prior autologous SCT and more lines of prior therapy. The relapse risk at 1 and 5 years was 51% and 53% respectively and was associated with use of a sibling donor. Disease status at transplant had no impact on the relapse rate. The progression free survival (PFS) was 41% and 36% at 1 and 5 years respectively with a trend to a higher PFS in patients under 45 years. The overall survival (OS) was 54% t 1 year and 42% at 5 years with a significantly better OS in CMV low risk transplants. Conclusion. BEAM-CAMPATH conditioning prior to allogeneic SCT is well tolerated in patients with aggressive NHL although there remains a significant relapse rate following this therapy. A significant minority of patients achieve durable disease free survival. The role of BEAM-CAMPATH allogeneic stem cell transplantation in these diseases warrants further investigation. Disclosures: No relevant conflicts of interest to declare.

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Motlló, Cristina, Josep-Maria Ribera, Mireia Morgades, Isabel Granada, Pau Montesinos, Santiago Mercadal, José González-Campos et al. « Frequency and Prognostic Significance of the Presence of Additional Cytogenetic Abnormalitions (ACA) to the Philadelphia (Ph) Chromosome in Young Adults with ACUTE Lymphoblastic Leukemia (ALL) Treated with the ALL Ph08 Trial from the Pethema Group ». Blood 128, n^o 22 (2 décembre 2016) : 1602. http://dx.doi.org/10.1182/blood.v128.22.1602.1602.

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Abstract Background. About 25-35% of adult patients with acute lymphoblastic leukemia (ALL) show the Philadelphia (Ph) chromosome. Their outcome has improved with the combination of tyrosine kinase inhibitors (TKI) and chemotherapy, generally followed by allogeneic hematopoietic stem cell transplantation (alloHSCT). However, few series have evaluated the prognostic value of the additional cytogenetic alterations (ACA) to the Ph chromosome, with contradictory results. The aim of this study was to analyse the frequency, type and prognostic significance of ACA to the Ph chromosome in young adults with Ph+ ALL treated with the ALL Ph-08 trial from the PETHEMA group. Patients and methods.Between 2008 and 2016, 95 patients with Ph+ ALL from 30 Spanish hospitals were included in the ALL Ph08 trial. This trial includes concurrent administration of imatinib (600 mg/d) and standard induction and consolidation chemotherapy, followed by alloHSCT (or autologous HSCT if alloHSCT not feasible) and maintenance chemotherapy with imatinib in cases of MRD persistence of reappearance after alloHSCT (Ribera et al, Br J Haematol 2012; 159: 78-81). The cytogenetic reports were centrally reviewed. Major molecular response (MMR) was defined as BCR-ABL/ABL ratio ²0.1% and complete molecular response (CMR) as BCR-ABL/ABL ratio ²0.01% or undetectable. Results. In 74 out of 95 patients the karyotype was evaluable after review (in the remaining 21 cases the diagnosis was carried out by FISH [n=9] or PCR [n=12]). The median age of the 74 patients was 39 years (limits 19-63) and 44 patients (59%) were males. The median WBC count was 17.6x109/L (limits 0.2-390) and 8 out of 66 evaluable patients had CNS involvement at diagnosis. The CR rate was achieved in 72/74 patients (97%) (1 patient did not achieve CR and 1 died during induction therapy). To date, 57 patients underwent to HSCT, of them 46 were in MMR, at least, at the time of HSCT. With a median follow-up of 1.89 years (limits 0.10-7.38) the probabilities of the CR duration, OS and EFS at 4 years were 69% (95%CI: 54%-84%), 39% (23%-55%) and 38% (23%-53%), respectively. Out of 74 patients, 52 (70%) showed at least one ACA and in the remaining 22 (30%) the t(9;22) was the only cytogenetic alteration. No clinical or biologic differences were observed on comparison of the two groups of patients. Twenty (27%) out of 73 evaluable patients showed trisomies and 19 (26%) monosomies. No differences in CR attainment were observed according the presence and type of ACA. The 4-yr. probability of CR duration in patients with t(9;22) and one or more monosomies (monosomal karyotype) vs. those without monosomies was 23% (95%CI: 0%;49%) vs. 88% (77%;99%) (p<0.001) and the 4-yr. EFS probability was 15% (95%CI: 0%;34%) vs. 48% (30%;66%) (p=0.032). Patients with one or more trisomies showed better CR duration probability at 4-years (86% [95%CI: 60%;100%] vs. 60% [42%-78%], p=0.040).The probability of CR duration was higher in patients who achieved MMR before HSCT (79% [63%-95%] vs. 38% [0%-77%], p=0.021). No other clinical or biologic parameter showed prognostic significance. By multivariate analysis the only variable with prognostic impact for CR duration and EFS was the presence of monosomal karyotype (HR [95%CI] 7.95 [2.04-30.95], p=0.003 and 2.18 [1.05-4.51], p=0.036, respectively). Conclusions. In young patients with Ph+ ALL treated within the ALL Ph08 trial, the frequency of ACA was high, being trisomies and monosomies shown in similar frequency. The monosomal karyotype was the most important unfavourable prognostic factor in this series of patients. Funded in part by grants PI10/01417 (FIS), RD12-0036-0029 from RTICC, Instituto Carlos III and RD14-SGR225(GRE), Generalitat de Catalunya. Figure Figure. Disclosures No relevant conflicts of interest to declare.

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Fields, Melanie E., Ari Berlin, Ronald Jackups, Monica L. Hulbert et Philip C. Spinella. « Red Blood Cell Storage Duration and Outcomes For Acute Chest Syndrome In Children and Young Adults With Sickle Cell Disease ». Blood 122, n^o 21 (15 novembre 2013) : 2246. http://dx.doi.org/10.1182/blood.v122.21.2246.2246.

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Abstract Introduction Red Blood Cells (RBCs) undergo physical and metabolic changes during storage. The clinical impact of the storage duration of transfused blood remains unclear. There is no published literature investigating the storage duration of transfused RBCs as it pertains to outcomes in patients with Sickle Cell Disease (SCD), yet surveys of RBC transfusion practices indicate that 50-60% of pediatric centers preferentially transfuse RBCs of shorter storage duration to patients with SCD. SCD patients with Acute Chest Syndrome (ACS) often require RBC transfusions to improve oxygenation and prevent or treat respiratory failure. The objective of our study is to determine if there is an association between the storage age of transfused RBCs and clinical outcomes for SCD patients with ACS. Methods In this retrospective cohort study, we included patients aged </= 22 years old with hemoglobin SS, hemoglobin SC, hemoglobin S-β0 thalassemia, hemoglobin S-β+ thalassemia or hereditary persistent fetal hemoglobin, diagnosed with ACS that were treated with at least one RBC transfusion between January 2007 and May 2012. We excluded episodes of ACS treated with exchange transfusion, and patients with a history of stem cell transplant or receiving chronic RBC transfusion therapy at the time of the ACS episode. ACS was defined as an infiltrate on chest x-ray consistent with a consolidation (not atelectasis) in addition to at least one of the following symptoms: cough, fever >/= 38.5 degrees Celsius, age-defined tachypnea, wheezing or chest pain. The primary outcome measure was length of hospital stay (LOS) after transfusion. Secondary outcomes included duration of supplemental oxygen and IV opioid utilization after transfusion. All analyses utilized the storage age of the oldest unit transfused per ACS episode if multiple units were given. Storage age of RBC units was dichotomized as less than or greater than 14 days, and less than or greater than 21 days (van de Watering, 2011). Outcomes were tested versus each resulting categorical variable. Multiple episodes of ACS in the same patient were analyzed as separate events. Non-parametric data is presented as median (interquartile range (IQR)). The Mann-Whitney U test was used to compare median values between groups tested. Future examination of the data will include generalized linear modeling with multivariate analysis. SPSS version 20 (Armonk, NY) was used for all statistical analyses. Results One hundred and forty-six episodes of ACS in 85 patients (46 male, 39 female, 77 HbSS, 1 HbSC, 4 Hb Sβ0, 1 Hb Sβ+, 2 HPFH) were included. Median (IQR) age of the patients was 8.9 (5.5-13.5) years. Median (IQR) storage age of the oldest unit of transfused RBCs was 18.5 (12.0-27.0) days. Median (IQR) volume transfused standardized by weight was 12.7 (10.6-16.9) mL/kg, with 29/146 (19.9%) receiving more than one RBC transfusion. In all 146 episodes of ACS, median (IQR) LOS after transfusion was 3.0 (2.0-5.0) days. Supplemental oxygen was required prior to transfusion in 109/146 (74.7%) of ACS episodes and for a median of 2.0 (1.0-3.0) days after transfusion. IV opioids were administered prior to transfusion in 93/146 (63.7%) of ACS episodes and for a median of 3.0 (2.0-6.0) days after transfusion. Table 1 describes outcomes compared with RBC age thresholds of 14 and 21 days. Conclusions We did not identify an association between storage duration of transfused RBCs and clinical outcomes in pediatric and young adult SCD patients with ACS in this hypothesis generating, retrospective cohort study. These preliminary data do not support the commonly practiced, preferential transfusion of RBCs of lesser storage duration in this population. Prospective, randomized, controlled trials are needed to determine if the common practice of transfusing RBCs of decreased storage age is beneficial in children and young adults with SCD. Disclosures: No relevant conflicts of interest to declare.

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Brady, Anna K., Alex Z. Fu, Marc Earl, Matt Kalaycio, Anjali Advani, Yogen Saunthararajah, Ronald Sobecks, Edward Copelan et Mikkael A. Sekeres. « Race and Intensity of Post-Remission Therapy in Acute Myeloid Leukemia (AML). » Blood 114, n^o 22 (20 novembre 2009) : 1012. http://dx.doi.org/10.1182/blood.v114.22.1012.1012.

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Abstract Abstract 1012 Poster Board I-34 Background: Disparities in survival between black and white patients (pts) exist for many malignancies, including AML. Potential causes include differential access to care; variable aggressiveness of therapy; and biological heterogeneity. Black men with AML have lower complete remission (CR) and overall survival (OS) rates than black women and whites, as shown in a previous Cancer and Leukemia Group B (CALGB) study in which induction therapies were defined, but subsequent treatment compliance and intensity was unknown. We investigated whether differences in post-remission therapy (PRT) might explain disparity in outcome. Methods: All pts with newly diagnosed AML treated with cytarabine-based induction therapy between 1997 and 2008 were included. PRT was defined as either cytarabine-based chemotherapy or bone marrow transplant (autologous or allogeneic) administered to pts achieving a CR and prior to relapse or in the setting of no relapse. PRT was coded according to intensity, in cumulative mg/m2 of cytarabine or mitoxantrone received, with BMT assigned the highest intensity of cytarabine. Data on known prognostic factors (age, white blood cell count (WBC) at diagnosis, pathologic subtype, AML etiology, cytogenetic risk groups (as defined by CALGB 8461)) were collected and controlled for in multivariable analyses. Time to PRT was measured in days from date of discharge after induction chemotherapy to date of PRT initiation, excluding patients with time to PRT >150 days, considered too long to be true consolidation. Comparisons between black and white pts were performed using linear, logistic, and proportional hazard regressions, exploring intensity of and time to PRT, and number of PRT cycles, along with potential interaction terms, controlling for known prognostic factors for outcome. Results: Of 460 pts, 421 had adequate data on PRT. Of these, 379 (90%) were white, 32 (8%) black, 10 (2%) other, and 46% were female. Similar to CALGB data, and compared to whites, blacks were younger (mean age 53.5 vs. 57.5 years, p=.11), had a higher proportion of favorable (18.8% vs. 12.7%) and poor risk (34.4% vs. 24.5%) cytogenetics (p=.28), and were less likely to attain a complete remission (CR, 66% vs. 73%, p=.39), though differences did not reach significance due to sample size. Other baseline characteristics, including reinduction rates, were similar. The 236 pts who received PRT included 18 blacks (56%) and 218 whites (58%, p=.89). In univariate analyses, for blacks vs. whites, median time to PRT initiation was 31 vs. 23 days (p=.33); cytarabine intensity was 66,654 mg/m2 vs. 50,630 mg/m2 (p=.26); and number of cycles was 2.4 vs. 2.1 (p=.41), respectively. Median time to PRT among all men was 24 days, compared to 21 days for all women (p=.09), and for pts <60 years was 22 days, vs. 24 days for >=60 years (p=.43). Median survival was 0.72 years in both black and white patients (p=.57). Among those receiving PRT, median survival was 3 years in blacks and 1.4 years in whites (p =.22); for pts not receiving PRT, median survival was.22 years in blacks and.32 years in whites (p =.25). In multivariate analyses, time to PRT was shorter for whites (HR=.25, p=.016), particularly when white men were compared to black men (HR=.12, p=.012), whereas no differences were found for women. Survival differences did not reach significance; nor was there an interaction for male and black race. Conclusions: Time to PRT is shorter for whites compared to blacks with AML, though cycle dose intensity and number are similar. Despite this, overall survival was not different between blacks and whites receiving PRT. In the post-remission setting, blacks and whites appear to receive similar chemotherapy management, and thus differential treatment aggressiveness and compliance are not explanations for varying outcome between races. Disclosures: No relevant conflicts of interest to declare.

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Zhao, Fang, Abhijit Barua et Jung Hoon Kim. « Consolidation of off-balance sheet entities and investment efficiency ». Accounting Research Journal ahead-of-print, ahead-of-print (2 septembre 2021). http://dx.doi.org/10.1108/arj-09-2020-0291.

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Purpose The purpose of this study is to examine the effect of consolidating off-balance sheet entities on firm-level investment efficiency. Financial Accounting Standards Board Interpretation No. 46, consolidation of variable interest entities – an Interpretation of ARB No. 51 (FIN 46) is used as a quasi-exogenous shock to financial reporting in this study. Design/methodology/approach The authors empirically test the change of investment efficiency for a sample of firms affected by FIN 46 in the post-FIN 46 periods. In the regression, a group of matched pairs selected from unaffected firms is used as the control sample and firm characteristics are used as control variables. Findings The authors find that firms affected by FIN 46 experience improvement in investment efficiency after adopting the standard compared to unaffected firms. The authors also document that FIN 46 firms’ level of investment decreases after FIN 46 compared to unaffected firms. These empirical results suggest that the improvement in investment efficiency is likely to be achieved by the reduction in over-investment. Further analyses show that amongst the affected firms, firms consolidating off-balance sheet special purpose entities (SPEs) improve investment efficiency mainly by reducing over-investment, whereas firms avoiding the consolidation of SPEs do not display such tendency. Originality/value This study contributes to the literature on the relation between financial reporting and investment efficiency, as well as the literature on the impact of FIN 46. To the best of the authors’ knowledge, this study is the first to examine the relation between the consolidation of off-balance sheet entities and investment efficiency.

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Reinstein, Alan, Gerald Lander et Stephen Danese. « Consolidation of Variable Interest Entities : Applying the Provisions of FIN 46 (R) ». SSRN Electronic Journal, 2005. http://dx.doi.org/10.2139/ssrn.815745.

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Bonsall, Samuel B., et Zahn Bozanic. « Ceteris Paribus ? Variable Interest Entity (VIE) Consolidation Under FIN 46R ». SSRN Electronic Journal, 2012. http://dx.doi.org/10.2139/ssrn.2152062.

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