scholarly journals Clinical Outcomes for Chronic Lymphocytic Leukemia (CLL) Patients with 11q Deletion in British Columbia (BC), Canada: Results of a Population-Based Cohort

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2648-2648
Author(s):  
Jennifer Goy ◽  
Tanya L. Gillan ◽  
Huang J.T. Steven ◽  
Helene Bruyere ◽  
Monica Anne Hrynchak ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Prognostic Markers ◽  
Clinical Course ◽  
Population Based ◽  
Trial Data ◽  
Disease Course ◽  
First Line ◽  
Prognostic Features ◽  
Significant Difference

Abstract BACKGROUND The 11q22.3 deletion (11q-) encompassing the ATM locus detected by fluorescence in situ hybridization (FISH) is present in up to 20% of CLL patients (pts), and is associated with an aggressive disease course and poor response to treatment (tx). However, there are few clinical studies that have specifically focused on pts with 11q-. Prognostic factors that may explain the variable outcome in this group have not been investigated, nor have survival outcomes in a population-based setting. Furthermore, few clinical studies have described practice patterns within the 11q- group. This study aims to improve our understanding of the prognosis, management and clinical course of CLL pts with 11q-. METHODS The BC Provincial CLL Database, which includes all pts who have undergone CLL FISH testing in a provincially validated laboratory since 2004, was used to identify all pts in BC (population 4.5 million) with a confirmed 11q- >10% found at any point during the disease course, with or without other detectable FISH abnormalities. Overall survival (OS), treatment-free survival (TFS) (time from diagnosis to first tx/death) and time to second-line treatment (tx) were the main outcomes of interest, and were investigated in relationship to age (<60 vs ≥60 years [yrs]), sex, Rai stage (3-4 vs 0-2), CD38 status, % 11q-, and presence of other recurrent FISH abnormalities (17p deletion [17p-], trisomy 12, 13q deletion, and IGH translocation). Multivariate analysis (MVA) was performed using Cox proportional hazard models with a backwards stepwise selection process to determine predictors of OS/TFS. RESULTS 125 out of 1044 (12%) pts were identified with 11q- detected at any point. Median age at CLL diagnosis was 61 yrs (range, 35-80). At a median follow-up of all patients of 6.3 yrs (range 0.5 - 26.2), median OS and TFS for the entire cohort are 12.6 yrs (standard error [SE] = 1.5 yrs) and 2.5 yrs (SE = 0.5 yrs), respectively. In MVA, advanced Rai stage (HR 3.7, 95% CI 1.28-10.8, P=.015), age ≥ 60 yrs (HR 2.2, 95% CI 1.2-4.3, P=.012) and male gender (HR 2.4, 95 % CI 1.5-5.3, P=.024) were significant predictors of OS. Clonal evolution (CE) to 11q- and/or other FISH abnormalities was documented in 12 pts. In 9/12 cases, 11q- developed after one or more tx courses whereas, in 3/12 cases, 11q- developed prior to tx initiation at median 5 yrs (range, 3.8-6.5) from initial FISH test. Sixty-nine pts had a documented 11q- pre-tx. At median follow-up of 5.0 yrs (range, 0.5 to 18.7), this group had median OS and TFS of 14.7 (SE =1.8) and 2.5 yrs (SE= 0.5), respectively (Fig 1). Pts with presence of 11q- and 17p- had a markedly worse prognosis compared to those without, with median OS 4.9 vs. 14.7 yrs (P< .001) and TFS of 0.2 vs. 2.5 yrs (P=0.31). In MVA, co-presence of 17p- (HR = 11.3, 95% CI 2.4-52.5, P=.02) and age ≥ 60 yrs (HR 3.8, 95% CI 0.83-17.1, P=.05) were adverse prognostic markers for OS. Age ≥ 60 yrs (HR =2.0, 95% CI 1.0-3.9, P=.03), presence of > 75% 11q- (vs. < 75 % 11q-) (HR = 1.8, 95%CI 1.0-2.3, P=.03) and advanced Rai stage (HR = 7.1, 95%CI 2.4-21.0, P=.01) were associated with shorter TFS. Of this group of 69, 52 pts (75%) received at least one tx course during follow-up. Thirty-three pts received fludarabine +/- rituximab (FR) as first line, 14 pts received alkylator based tx (FC +/- R in 8; CVP +/- R in 5; CHOP + R in 1) and 5 pts received chlorambucil-based +/- R. Pts treated with FR alone had median OS 12.8 yrs (SE=1.0), which was not statistically different from those treated with alkylators , where median OS was 6.8 yrs (SE=2.1), P=.35 (Fig 2). In MVA, receipt of fludarabine vs alkylator-based treatment was not associated with any significant difference in OS (P=.52) or time to 2nd tx (P=.65). CONCLUSION This study is to our knowledge the largest population-based report of CLL pts with 11q- and further enhances our understanding of the clinical course of such pts in a real world setting. Although median TFS of 11q- pts is short at 2.5 yrs, OS remains long at 12.6 yrs. The importance of combined 11q- and 17p- as adverse prognostic markers in CLL is highlighted. Most pts in BC with 11q- received FR as first line therapy. There is retrospective trial data suggesting that first line tx containing alkylators (ie. cyclophosphamide) can overcome the adverse prognostic features of 11q-. However, most of this trial data is from the pre-R era. Though limited in numbers, our study does not suggest that first line tx without alkylators is associated with negative outcomes. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Toze: Roche: Consultancy, Honoraria, Research Funding. Gerrie:F Hoffmann-La Roche: Other.

Does Hospitalization Predict the Disease Course in Ulcerative Colitis? Prevalence and Predictors of Hospitalization and Re- Hospitalization in Ulcerative Colitis in a Population-based Inception Cohort (2000-2012)

2015 ◽  
Vol 24 (3) ◽  
pp. 287-292 ◽  
Author(s):  
Petra A. Golovics ◽  
Laszlo Lakatos ◽  
Michael D. Mandel ◽  
Barbara D. Lovasz ◽  
Zsuzsanna Vegh ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Cox Regression ◽  
Diagnostic Procedures ◽  
Population Based ◽  
Disease Course ◽  
Inception Cohort ◽  
Disease Extent ◽  
Cox Regression Analysis ◽  
Hospitalization Rates

Background & Aims: Limited data are available on the hospitalization rates in population-based studies. Since this is a very important outcome measure, the aim of this study was to analyze prospectively if early hospitalization is associated with the later disease course as well as to determine the prevalence and predictors of hospitalization and re-hospitalization in the population-based ulcerative colitis (UC) inception cohort in the Veszprem province database between 2000 and 2012. Methods: Data of 347 incident UC patients diagnosed between January 1, 2000 and December 31, 2010 were analyzed (M/F: 200/147, median age at diagnosis: 36, IQR: 26-50 years, follow-up duration: 7, IQR 4-10 years). Both in- and outpatient records were collected and comprehensively reviewed. Results: Probabilities of first UC-related hospitalization were 28.6%, 53.7% and 66.2% and of first re-hospitalization were 23.7%, 55.8% and 74.6% after 1-, 5- and 10- years of follow-up, respectively. Main UC-related causes for first hospitalization were diagnostic procedures (26.7%), disease activity (22.4%) or UC-related surgery (4.8%), but a significant percentage was unrelated to IBD (44.8%). In Kaplan-Meier and Cox-regression analysis disease extent at diagnosis (HR extensive: 1.79, p=0.02) or at last follow-up (HR: 1.56, p=0.001), need for steroids (HR: 1.98, p<0.001), azathioprine (HR: 1.55, p=0.038) and anti-TNF (HR: 2.28, p<0.001) were associated with the risk of UC-related hospitalization. Early hospitalization was not associated with a specific disease phenotype or outcome; however, 46.2% of all colectomies were performed in the year of diagnosis. Conclusion: Hospitalization and re-hospitalization rates were relatively high in this population-based UC cohort. Early hospitalization was not predictive for the later disease course.

scholarly journals Metformin use and long-term risk of benign prostatic hyperplasia: a population-based cohort study

BMJ Open ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. e041875
Author(s):  
Mette Nørgaard ◽  
Bianka Darvalics ◽  
Reimar Wernich Thomsen
Keyword(s):  
Cohort Study ◽  
Benign Prostatic Hyperplasia ◽  
Cox Regression ◽  
Population Based ◽  
Prostatic Hyperplasia ◽  
Haemoglobin A1c ◽  
First Line ◽  
Intention To Treat ◽  
Lowering Drug

ObjectiveTo assess whether metformin use affects risk of benign prostatic hyperplasia (BPH) by comparing the risk of BPH in men with type 2 diabetes who initiated first-line treatment with either metformin or sulfonylurea monotherapy between 2000 or 2006 in Northern Denmark. In this period, sulfonylurea and metformin were both frequently used as first-line glucose-lowering drug (GLD) treatment.DesignA population-based cohort study.SettingNorthern Denmark.ParticipantsAll men who filled at least two prescriptions for metformin or for sulfonylurea, respectively, during their first 6 months of GLD treatment. Follow-up started 6 months after treatment start.Primary outcome measuresRates of subsequent BPH, identified based on community prescriptions for BPH-related treatment or hospital BPH diagnoses, and rates of transurethral resection of the prostate (TURP). Rates in metformin and sulfonylurea users were compared overall and stratified by 6-month haemoglobin A1c (HbA1c) using Cox regression and an intention-to-treat (ITT) approach and an as-treated analysis.ResultsDuring follow-up, less than five persons were lost to follow-up due to emigration. In 3953 metformin initiators with a median follow-up of 10 years, the 10-year cumulative BPH incidence was 25.7% (95% CI 24.2 to 27.1). Compared with 5958 sulfonylurea users (median follow-up 8 years, 10-year cumulative incidence 27.4% (95% CI 26.2 to 28.6)), the crude HR for BPH was 0.83 (95% CI 0.77 to 0.89) and adjusted HR in the ITT analyses was 0.97 (95% CI 0.88 to 1.06). For TURP, the adjusted HR was 0.96 (95% CI 0.63 to 1.46). In the as-treated analysis, adjusted HR for BPH was 0.91 (95% CI 0.81 to 1.02).ConclusionsCompared with sulfonylurea, metformin did not substantially reduce the incidence of BPH in men with diabetes.

scholarly journals Effect of Genetic and Laboratory Findings on Clinical Course of Antisynthetase Syndrome in a Hungarian Cohort

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Katalin Szabó ◽  
Levente Bodoki ◽  
Melinda Nagy-Vincze ◽  
Anett Vincze ◽  
Erika Zilahi ◽  
...  
Keyword(s):  
Prognostic Markers ◽  
Clinical Course ◽  
Disease Onset ◽  
Skin Lesions ◽  
Clinical Database ◽  
Laboratory Findings ◽  
Disease Phenotypes ◽  
Genetic Features ◽  
Hla Dqa1

The aim of this study was to determine the clinical, serological, and genetic features of anti-Jo-1 positive antisynthetase patients followed by a Hungarian single centre to identify prognostic markers, which can predict disease phenotypes and disease progression. It was a retrospective study using clinical database of 49 anti-Jo-1 positive patients. 100% of patients exhibited myositis, 73% interstitial lung disease, 88% arthritis, 65% Raynaud’s phenomenon, 43% fever, 33% mechanic’s hand, and 12% dysphagia. We could detect significant correlation between anti-Jo-1 titer and the CK and CRP levels at disease onset and during disease course. HLA DRB1⁎03 positivity was present in 68.96% of patients, where the CK level at diagnosis was significantly lower compared to the HLA DRB1⁎03 negative patients. HLA DQA1⁎0501-DQB1⁎0201 haplotype was found in 58.62% of patients, but no significant correlation was found regarding any clinical or laboratory features. Higher CRP, ESR level, RF positivity, and the presence of fever or vasculitic skin lesions at the time of diagnosis indicated a higher steroid demand and the administration of higher number of immunosuppressants during the follow-up within anti-Jo-1 positive patients. The organ involvement of the disease was not different in HLA-DRB1⁎0301 positive or negative patients who were positive to the anti-Jo-1 antibody; however, initial CK level was lower in HLA-DRB1⁎0301 positive patients. Distinct laboratory and clinical parameters at diagnosis could be considered as prognostic markers.

scholarly journals Does CSF pleocytosis have a predictive value for disease course in MS?

2019 ◽  
Vol 6 (5) ◽  
pp. e584 ◽  
Author(s):  
Itay Lotan ◽  
Felix Benninger ◽  
Rom Mendel ◽  
Mark A. Hellmann ◽  
Israel Steiner
Keyword(s):  
Clinical Course ◽  
Medical Center ◽  
Oligoclonal Bands ◽  
Disease Course ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Csf Pleocytosis ◽  
Csf Oligoclonal Bands ◽  
Rabin Medical

ObjectiveMS is a demyelinating CNS disorder with a spectrum of clinical patterns regarding course and prognosis. Although several prognostic factors are considered in the initial evaluation of patients, biological markers defining the disease course and guiding treatments are currently lacking. It is unknown whether patients with CSF pleocytosis differ in regard to symptoms, disease course, and prognosis from those without. The aim of this study was to evaluate whether CSF pleocytosis during the initial presentation has an impact on the clinical course and progression of MS.MethodsWe retrospectively evaluated patients attending the MS Clinic at Rabin Medical Center between January 1999 and January 2016 who underwent lumbar puncture (LP) at disease presentation, considering CSF cell count, clinical diagnosis (clinically isolated syndrome [CIS] and relapsing-remitting MS [RRMS]), annualized relapse rate (ARR), paraclinical findings (imaging, CSF oligoclonal bands, and evoked potentials), and disease progression, expressed by the Expanded Disability Status Scale (EDSS).ResultsOne hundred fourteen patients (72 females) underwent LP at disease presentation (RRMS: n = 100, CIS: n = 14). Age at diagnosis was 32.4 ± 12.2 years, and the follow-up time was 9.4 ± 3.8 years. Forty-six patients showed a pleocytic CSF (≥5 cells per μL). Compared with patients with <4 cells per μL, patients with pleocytosis had a higher ARR (0.60 ± 0.09 vs 0.48 ± 0.04; p = 0.0267) and a steeper increase (slope) in the EDSS score throughout the follow-up period (correlation coefficient: r2 = 0.04; p = 0.0251).ConclusionsCSF pleocytosis may be considered a biological unfavorable predictive factor regarding disease course and progression in MS.

scholarly journals Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality

Blood ◽  
2020 ◽  
Vol 135 (4) ◽  
pp. 261-268 ◽  
Author(s):  
Jakob Werner Hansen ◽  
Dorthe Almind Pedersen ◽  
Lisbeth Aagaard Larsen ◽  
Simon Husby ◽  
Signe Bedsted Clemmensen ◽  
...  
Keyword(s):  
Genetic Predisposition ◽  
Population Based ◽  
Specific Gene ◽  
Variant Allele Frequency ◽  
Population Based Study ◽  
Clonal Hematopoiesis ◽  
Significant Difference ◽  
Significant Heritability ◽  
Gene Subgroup

Abstract Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is defined by mutations in myeloid cancer–associated genes with a variant allele frequency of at least 2%. Recent studies have suggested a possible genetic predisposition to CH. To further explore this phenomenon, we conducted a population-based study of 594 twins from 299 pairs aged 73 to 94 years, all with &gt;20 years’ follow-up. We sequenced DNA from peripheral blood with a customized 21-gene panel at a median coverage of 6179X. The casewise concordance rates for mutations were calculated to assess genetic predisposition. Mutations were identified in 214 (36%) of the twins. Whereas 20 twin pairs had mutations within the same genes, the exact same mutation was only observed in 2 twin pairs. No significant difference in casewise concordance between monozygotic and dizygotic twins was found for any specific gene, subgroup, or CHIP mutations overall, and no significant heritability could be detected. In pairs discordant for CHIP mutations, we tested if the affected twin died before the unaffected twin, as a direct measurement of the association of having CH when controlling for familial factors. A total of 127 twin pairs were discordant for carrying a mutation, and in 61 (48%) cases, the affected twin died first (P = .72). Overall, we did not find a genetic predisposition to CHIP mutations in this twin study. The previously described negative association of CHIP mutations on survival could not be confirmed in a direct comparison among twin pairs that were discordant for CHIP mutations.

Allogeneic Stem Cell Transplantation (SCT) with Non Myeloablative Conditioning Regimen (NST) Following Intensive Consolidation May Be Equivalent to Conventional alloSCT and Superior to autoSCT for Patients over 50 with Acute Myeloid Leukemia (AML) in 1stCR: First Results of the AML 2001 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 319-319 ◽  
Author(s):  
B. Lioure ◽  
J. Delaunay ◽  
D. Blaise ◽  
N. Milpied ◽  
P. Guardiola ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Phase Iii ◽  
Late Relapse ◽  
Marrow Graft ◽  
Hematopoietic Stem ◽  
Prognostic Features ◽  
Significant Difference ◽  
First Results ◽  
Alternative Sources

Abstract From 11/01 until 04/05, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were included in prospective phase III AML 2001 trial. After achieving CR, research to identify an HLA-identical sibling was performed for all patients as they received low dose consolidation (Daunorubicin (D): 60 mg/m2 × 2d OR Idarubicin (I): 12 mg/m2 × 2d plus SC ARAC 100 mg/m2 ×7d). 33 % patients had a donor then could proceed to a T-replete alloSCT: either conventional if age ≤ 50 (bone marrow graft; conditioning regimen: TBI (12 Gy 6 fractions over 3d) - cyclophosphamide (60 mg/kg × 2d); GvHD prophylaxis: ciclosporin-methotrexate d1+3+6) = arm M; or NST if age 51–60 (peripheral blood; Busulfan (oral Bu 4–8 mg/kg over 2d) - Fludarabin (30 mg/m2 × 4d) – Thymoglobulin® (2,5 mg/kg × 2d); ciclosporin alone), AFTER intensive consolidation (D: 60 mg/m2 × 2d OR I: 12 mg/m2 × 2d plus ARAC 3 g/m2 × 8 doses over 4d) = arm m. A small group of patients with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction = 3% CR1 patients) didn’t receive 1st line alloSCT but intensive consolidation then a 2nd HD ARAC course; alloSCT was therefore considered at relapse = arm C. Patients without donor proceed to intensive consolidation then 1 or 2 autoSCT (1st after HDM 200 mg/m2 according to randomization, then Bu 16 mg/kg over 4d + HDM 140 mg/m2 for all patients) = arms A + B; they were combined for analysis as no difference was observed for DFS and OS. Actual results concern 532 patients with 15 months follow-up (A + B = 367; M = 111; m = 54). Median age was different between 3 groups (A + B = 46; M = 40; m = 54) as no difference was observed regarding leukocytosis or cytogenetic subgroups: favorable (t8;21) or inv16: A + B = 15%; M = 11%; m = 11%), intermediate (A + B = 72%; M = 78%; m = 67%), defavorable (5, 7, complex, 11q23 except t(9;11) or 3q; A + B = 13%; M = 11%; m = 22%). Conventional alloSCT results in better 2y DFS than autoSCT arms (M 71% vs A+B 52%, p=0,007) thought 2y OS advantage remains non significant (M 77% vs A+B 68%, p=0,06) as toxic death rate is higher (36% all deaths in arm M vs 14 % in arms A + B). No significant difference was observed between conventional alloSCT and NST (2y DFS 62%, OS 68%). Advantage for NST over autoSCT arms was non significant for DFS (p=0,24) and OS. Same results are obtained if considering only patients aged > 50: 2y EFS (m 62% vs A+B 50%, p=0,27) and OS (m 68% vs A+B 65%). After NST, toxicity accounts for 25% deaths, as relapse rate is 40% at 2y with no late relapse thereafter (vs 48 % at 2y and 61 % at 4y in arms A + B). In conclusion: 1) conventional alloSCT remains the best consolidation treatment for patients ≤ 50 with AML in CR1 despite higher toxicity; 2) NST after intensive consolidation seems promising: for older patients as toxicity is lower than conventional alloSCT, as few late relapse are observed in comparison with chemotherapy or autoSCT approaches; 3) NST may extend use of alternative sources of allogeneic hematopoietic stem cells to propose alloSCT approach for the majority of patients ≤ 60 with AML in CR1. Data with more than 2 years follow-up will be presented.

No Benefit of Adding High-Dose Melphalan (HDM) Suppported by Autologous Stem Cell Transplantation (SCT) over Treatment with Conventional Induction, HD ARAC Consolidation, and Auto SCT (Busulfan + HDM) for Acute Myelogenous Leukemia (AML) under 60: First Results of the Randomized AML 2001 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 608-608 ◽  
Author(s):  
B. Lioure ◽  
A. Pigneux ◽  
C. Recher ◽  
F. Witz ◽  
T. Lamy ◽  
...  
Keyword(s):  
Early Death ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Marrow Graft ◽  
Prognostic Features ◽  
Frequent Use ◽  
Significant Difference ◽  
First Results ◽  
High Dose Melphalan

Abstract From 11/2001 until 04/2005, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were 1st randomized to received induction with continuous IV ARAC (200 mg/m2, x 7d) and Daunorubicin (D: 60 mg/m2 x 3d) OR Idarubicin (I: 8 mg/m2 x 5d). If marrow blasts &gt; 5% on D15, 2nd induction course was applied (D: 35 mg/m2 x 2d OR I: 8 mg/m2 x 2d plus ARAC 1 g/m2 x 4 doses over 2d). After achieving CR, all patients received low dose consolidation (D: 60 mg/m2 x 2d OR I: 12 mg/m2 x 2d plus SC ARAC 100 mg/m2 x 7d). Patients with HLA-identical sibling receive a T-replete alloSCT: either conventional (bone marrow graft, TBI-cyclophosphamide, ciclosporin-methotrexate) if age ≤ 50 = arm M; or non myeloablative (NST: peripheral blood, Busulfan (Bu)-Fludarabin-Thymoglobulin®, ciclosporin alone), AFTER intensive consolidation (idem below) if age 51–60 = arm m. A small subgroup of patients (3 % patients in CR) with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction) did not receive 1st line alloSCT but intensive consolidation then a 2nd HD ARAC course; alloSCT was therefore considered for relapse = arm C. Other patients proceed to 2nd randomization: intensive consolidation (D: 60 mg/m2 x 2d OR I: 12 mg/m2 x 2d plus ARAC 3 g/m2 x 8 doses over 4d) PLUS 1 autoSCT (Bu 16 mg/kg over 4d + HDM 140 mg/m2) = arm A; or intensive consolidation PLUS 2 autoSCT (HDM 200 mg/m2 THEN Bu 16 mg/kg over 4d + HDM 140 mg/m2) = arm B. After 1st randomization (D vs I), no difference was observed between 2 arms regarding age, leukocytosis or cytogenetic subgroups: favorable (t8;21) or inv16: D = I 13%), intermediate (D 66%, I 59%), defavorable (5, 7, complex, 11q23 except t(9;11) or 3q; D 21%, I 28%). Use of both anthracyclins results in same CR rate (D 83% vs I 85%); early death (3%); projected EFS (D 46% vs I 50%, p = 0,28) and OS (D 61% vs I 64%) at 2 years. Noteworthy was the more frequent use of 2nd induction course to obtain CR with D (30%) as compared with I (22%). 78% of all patients in CR proceeded to 2nd randomization or were assigned to alloSCT arms (33 % of them). Actual results concern 550 patients with 15 months follow-up. No benefit was observed with addition of HDM 200 for 2y projected DFS (A 53% vs B 49%) or OS (A = B 68%). Toxic death rate was higher in arm B, accounting for 18% total deaths vs 6% in arm A. Conventional alloSCT results in better 2y DFS than combined arms A+B (M 71% vs A+B 52%, p=0,007) thought 2y OS advantage remains non significant (M 77% vs A+B 68%, p=0,06). No significant difference was observed between conventional and NST (2y DFS 62%, OS 68%). Advantage for NST over autoSCT arms was non significant for DFS (p=0,24) and OS. Same results are obtained if considering only patients aged &gt; 50 : 2y EFS (m 62% vs A+B 50%, p=0,27) and OS (m 68% vs A+B 65%). In conclusion: conventional alloSCT remains the best consolidation treatment for patients ≤ 50 with AML in CR1; NST after intensive consolidation seems promising for older patients and may extend use of alternative sources of alloSCT; HDM course adds no benefit for these patients. Data with more than 2 years follow-up will be presented.

Long Term Follow up of Patients with CML in Chronic Phase Treated with First-Line Imatinib Suggests That Earlier Achievement of a Major Molecular Response Leads to Greater Stability of Response.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2113-2113 ◽  
Author(s):  
Susan Branford ◽  
Rebecca Lawrence ◽  
Andrew Grigg ◽  
John Francis Seymour ◽  
Anthony Schwarer ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Low Risk ◽  
Initial Slope ◽  
Molecular Response ◽  
Average Dose ◽  
Major Molecular Response ◽  
First Line ◽  
Significant Difference

Abstract A major molecular response (MMR) by 12 or 18 months (m) of standard dose imatinib for patients (pts) with newly diagnosed chronic phase CML is associated with a low risk of progression to accelerated phase or blast crisis. Phase II/III trials suggest that MMR may be achieved earlier with higher doses of imatinib. We determined whether the timing of MMR affects the long term stability of response with regard to the acquisition of BCR-ABL mutations and/or loss of MMR (collectively defined as an “event”) for pts with up to 8 years of follow up since commencing first-line imatinib. All pts treated with 400 to 600mg of first-line imatinib who were monitored regularly at our institution for BCR-ABL levels by real-time quantitative PCR and mutation analysis by direct sequencing were evaluated: 181 pts were followed for a median of 45m (range (r) 3–96m). The event rate was compared for pts dependent on the time to MMR (≤0.1% IS (international scale)) in 6m intervals to 18m of imatinib. The events for pts with undetectable BCR-ABL (complete molecular response, CMR) were also determined. Strict sensitivity criteria were used for CMR: undetectable BCR-ABL where the sensitivity of analysis indicated BCR-ABL was &lt;0.003% IS, (equivalent to at least 4.5 log below the standardized baseline) which was confirmed on a subsequent analysis. Loss of MMR was defined as a confirmed &gt;2 fold rise from nadir to a level &gt;0.1% IS in pts who maintained imatinib dose. 144/181 pts (80%) achieved MMR at a median of 12m (r 3–53m). Consistent with other studies, maintaining a higher dose of imatinib in the first 6m of therapy was associated with a significantly higher frequency of pts achieving MMR by 6m. 118 pts received an average dose of &lt;600mg in the first 6m and 18/118 (15%) achieved MMR by 6m, whereas 63 pts received an average dose of 600mg in the first 6m and 23/63 (37%) achieved MMR by 6m, P=0.002. Mutations were detected in 14/181 pts (8%) at a median of 9m (r 3–42m). An event occurred in 8 pts with MMR at a median of 36m (r12–57m) after commencing imatinib, including one patient who had achieved CMR. Mutations were found in 4 pts and 3/4 lost MMR. The remaining 4 lost MMR without a mutation. The one patient with a mutation who did not lose MMR had a 3-fold rise in BCR-ABL at the time of mutation detection and responded to a higher imatinib dose. The other pts with mutations had therapeutic intervention upon cytogenetic relapse (2) or loss of MMR (1). The 4 pts with loss of MMR and no mutation had accelerated phase (1), cytogenetic relapse (2) and one maintained CCR with 3m of follow up. The median fold rise in BCR-ABL upon loss of MMR was 26 (r 4–220). The probability of an event if MMR was achieved by a) 6m was 0% (n=41 evaluable pts), b) &gt;6 to 12m was 12% (n=40) and c) 12 to 18m was 19% (n=33). The median follow up since MMR was achieved was not significantly different for the groups: 49m (r 3–87m), 38m (r 6–87m), 40m (r 9–78m), respectively, P=0.5. The risk of an event for pts with MMR achieved by 6m was significantly lower than in pts with MMR achieved by &gt;6 to 18m, P=0.04. CMR occurred in 55 pts who were followed for a median of 24m (r 3–55m) after its attainment. Only 1 event occurred in these 55 pts, which was at 6m after CMR was achieved and 57m after commencing imatinib. This patient had maintained MMR for 45m but loss of a major cytogenetic response occurred 6m after loss of MMR. There was a significant difference in the probability of CMR by 60m of imatinib dependent on the time to MMR, P&lt;0.0001 (Figure). All pts failed to achieve CMR by 60m if not in MMR at 18m whereas the actuarial rate of CMR at 60m was 93% in those with MMR by 6m. The initial slope of BCR-ABL decline correlated strongly with the decline over the longer term. The mean time to CMR after attainment of MMR was significantly faster for pts with MMR by 6m compared to those with MMR at &gt;6 to 12m and &gt;12 to 18m: 24m vs 37m vs 42m, respectively, P=0.001. This suggests the rate of BCR-ABL reduction below the level of MMR was faster in pts with MMR by 6m, which may be clinically beneficial as none of these pts had a subsequent event. Based on these findings we propose that inducing earlier molecular responses with higher dose imatinib or more potent kinase inhibitors may lead to more durable and deeper responses. It remains possible however, that early molecular response reflects a more biologically favourable disease rather than being the direct cause of more durable response. Finally, CMR was associated with an extremely low risk of events, making it an appropriate next target of therapy after MMR is achieved. Figure Figure

Prognostic Impact of Clinical and Tumor Associated Variables in a Population-Based Cohort of Mantle Cell Lymphomas in the Stockholm Region Between 1998–2010

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1592-1592 ◽  
Author(s):  
Stefanie Baumgartner Wennerholm ◽  
Monika Klimkowska ◽  
Lina Nygren ◽  
Eva Kimby ◽  
Birgitta Sander
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Median Survival ◽  
Biological Markers ◽  
Population Based ◽  
Prognostic Impact ◽  
Female Ratio ◽  
Significant Difference ◽  
Mantle Cell

Abstract Abstract 1592 Introduction: Mantle cell lymphoma (MCL) constitutes 3–10% of non-Hodgkin lymphomas and affects predominantly middle-aged to elderly men. The median survival is 3–5 years and seems to improve with new therapeutic regimens. The MCL International Prognostic Index (MIPI) has been proven useful for predicting survival in MCL patients included in clinical trials, but its value in unselected population based MCL cohorts is less well known. Biological markers are increasingly used for prognostication of MCL patients, especially for defining indolent cases. Material and Methods: All 186 patients diagnosed with MCL, confirmed by IHC for cyclinD1 and/or by FISH for t(11;14), between January 1998 and June 2010 in the Stockholm region, were included in a retrospective analysis. Clinical data from patient files, diagnostic biopsies and flow cytometry data were reviewed. Last follow-up was in May 2011. The prognostic value of the following variables, evaluated at the time of diagnosis, were analyzed: age, sex, Ann Arbor stage, ECOG, B-symptoms, Hb, LDH, albumin, lymphocytosis, leukocytosis, splenomegaly, nodal, extranodal and bone marrow involvement, blastoid morphology, expression of CD23, light chain, Ki 67, p53 and nuclear SOX11. Results: The median age at diagnosis was 68.8 years (range 36.2 – 89.9); 67.4 in males and 72.1 in females, respectively. The male: female ratio was 2. Thirty patients had a known malignancy of other type before the MCL diagnosis and 12 acquired a cancer later. In 13 patients the other malignancy was the cause of death. Median overall survival (OS) time was 43 months in the whole cohort and 38 months, when excluding 39 patients receiving ASCT as part of first-line therapy. No statistically significant difference in OS was seen with respect to whether the lymphoma was diagnosed before or after 2005. In the non-transplanted patients (n=149), univariate analysis showed the following clinical variables to be negatively correlated to overall survival: age >65 years, B-symptoms, splenomegaly, ECOG >2, low albumin, and high LDH. The median survival was not reached in the low risk MIPI group, and was 79 and 34 months, in the middle and high risk MIPI group, respectively. Blastoid morphology and p53 positivity (>20%), were negatively correlated to overall survival (both with p<0.0001), as was increasing tumor cell proliferation (measured as a continous variable or using the cut-offs >50%, both with with p<0.0001), but not with cut-off >30% (p=0.061), while SOX11 positivity was related to a prolonged survival (p=0.015). Multivariate analyses showed that age >65 (HR 6.1, p<0,002), ECOG >2 (HR 63, p<0.001), high LD (HR 3.7, p< 0.001), and p53 positivity (HR 5.6, p< 0.0001) remained significant. Clinically indolent MCL, defined as in retrospect not requiring treatment within two years from diagnosis, was seen in 17 patients. In two of these patients the proliferation was >30%, in one >50%, two had a p53 expression >20% and two were SOX11 negative. Therapy was never required in 9 of these initially indolent patients and only one had an autologous transplantion later in the disease course. The median OS was 72 months for the 17 indolent MCL compared with 34 months in patients requiring treatment earlier in their disease (p=0.003). The follow-up time did not differ significantly between the two groups. Conclusions: Compared to data from published clinical trials of advanced MCL, our population-based cohort of 186 cyclin D1 positive MCL patients were diagnosed at an older age, which may contribute to a shorter overall survival. Certain well-established prognostic variables seem to loose significance outside study populations. In the group of 147 non-transplanted patients multivariate analysis showed that only age, ECOG, LDH and p53 positivity were independently associated with overall survival. Leukocytosis as a variable of MIPI had no impact. Neither SOX11, CD23 or other biological markers applied at the time of diagnosis could predict for clinically indolent disease. Disclosures: No relevant conflicts of interest to declare.

Treatment Sequencing and Efficacy in Newly Diagnosed Non-Transplant Eligible Myeloma Patients in the Netherlands: A Population Based Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4284-4284 ◽  
Author(s):  
S GR Verelst ◽  
Y van Norden ◽  
H M Blommestein ◽  
J Roobol ◽  
M Schoenmaker ◽  
...  
Keyword(s):  
The Netherlands ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Population Based ◽  
Response To Treatment ◽  
Age Group ◽  
First Line ◽  
Treatment Regimens ◽  
Significant Difference ◽  
Treatment Sequences

Abstract Abstract 4284 Background The introduction of immunomodulatory drugs (IMiDs) and proteosome-inhibitors changed the treatment strategies for non-transplant eligible myeloma patients in the last decade. Results on efficacy of these treatment regimens result primarily from randomized controlled trials. Population based results on treatment sequences and efficacy of the different treatment regimens are sparse but necessary to provide complementary information from daily practice. Method PHAROS, the Population based Haematological Registry in the Netherlands collects detailed information on patient characteristics, treatment and response to treatment of myeloma patients. We studied treatment sequences for non-transplant eligible patients above 65-years diagnosed between January 2004 and December 2009 in the South West of the Netherlands. Although data collection in the PHAROS registry is ongoing, the mentioned subset in this region is (almost) complete. The treatment regimens were divided into five main groups: 1) proteosome-Inhibitor based; 2) IMiD-based; 3) combination of proteosome-inhibitor and IMiD, 4) alkylating-based and 5) other (including steroid based). We determined the number of treatment lines and the sequence of the treatment regimens. Overall survival (OS) was analysed in the whole group, by type of first line regimen and by age group (66–69 years; 70–79 years; 80+ years) using Kaplan-Meier. Subgroup differences were also analysed using Cox regression. Results 408 patients were included with a median follow up time of 45 months. Mean age at diagnosis was 76-years (range 66–99) and 53% of the patients were male. 59% had stage IIIA/B at diagnosis, 13% previous MGUS. 87 % of patients had WHO 0–2. There was large diversity in number of pre-existing co-morbidities: ranging from 14% without any to 20% having 3 or more co-morbidities at diagnosis. 11% of the patients participated in trial setting for initial treatment. Of the whole group 24% received at least two lines of treatment and 8% at least three since diagnosis. 16% of the patients did not receive treatment so far: 52% because of smouldering myeloma; 33% because of refusal of patients, short life expectancy or poor functional status. 23% of the last group of patients without treatment was 80+ years of age. Choice of treatment regimens was significantly related with age and year of diagnosis. For patients diagnosed between 2004 and 2006, more patients of age 66–69 received an IMiD-based first line than patients aged 70–79 and they, in turn, received more often an IMiD based as patients of 80+ years of age (40% versus 26% versus 12% respectively). Patients of 80+ years of age mainly received an alkylating based 1st line treatment (73%). In the period 2007–2009 an increase in IMiD-based 1st line was observed (69% overall: 63%, 77% and 58% respectively per age group). 13% of patients aged 66–69 received proteosome-inhibitor based 1st line compared to 1% of the patient aged 70–79 and non of patients aged 80+. Patients receiving an alkylating-based 1st line 70% of them received an IMiD-based 2nd line. If patients received an IMiD-based 1st line 54% of them received a proteosome-inhibitor based 2nd line and 29% again an IMiD-based 2nd line. If patients received an alkylating 2nd line, 56% than received an IMiD-based 3rd line. 83% of patients who had proteosome-inhibitor based 2nd line received an IMiD based 3rd line. 59% of the patients who had received IMiD based 2nd line received a proteosome-inhibitor based 3rd line. OS significantly improved when patients received IMiD in 1st line compared to alkylating (p=0.03, HR 0.73). This improvement was seen for all patients up to 80 years of age. We observed significant difference in OS between the age groups (p<.001) with median survival of 13 months for patients aged 80+ to 40 months for patient aged 66–69 years. WHO performance status was also significant (p <0.001) related with OS while number co-morbidities at diagnosis did not have significant impact (p=0.07). Conclusion Population based results seem to confirm the significant improvement in OS of IMiD-based regimens in 1st line compared to alkylating based for elderly patients. An increase in the use of IMiD based 1st line regimens was observed for patients diagnosed since 2007. While there is large treatment diversity we observed a sequence ordering in treatment lines from alkylating based followed by IMiD-based followed by proteosome-inhibitor based regimens. Disclosures: No relevant conflicts of interest to declare.

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