Excellent Long-Term Survival of Patients with Waldenström‘s Macroglobulinemia (WM) treated in Private Oncology Practices and a University hospital with different Treatment Strategies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2671-2671
Author(s):  
Manfred Hensel ◽  
Jürgen Brust ◽  
Christoph Plöger ◽  
Dieter Schuster ◽  
Marie-Luise Memmer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Standard Treatment ◽  
Clinical Symptoms ◽  
B Cell Lymphoma ◽  
Immunoglobulin M ◽  
University Hospital ◽  
Term Survival ◽  
Significant Difference ◽  
Time To First Treatment

Abstract Abstract 2671 Background: WM is a rare type of malignant B-cell lymphoma, defined as a lymphoplasmocytic lymphoma in bone marrow and a monoclonal gammopathy of immunoglobulin-M (IgM) type. Due to the paucity of large clinical trials, a standard treatment regimen is still controversial. The purpose of this study was to compare the standard treatment and outcome of patients (pts) treated in private oncology practices (PP) and a university hospital (UH) in a region of southern Germany (Nordbaden). Methods: We retrospectively reviewed the charts of all pts with WM of the last 2 decades of 4 PP in Mannheim, Heidelberg, Karlsruhe and Speyer and the department of hematology of the University of Heidelberg. Results: 170 patients with WM could be identified, 74 from PP, 96 from the UH. The median age of the 170 pts was 63.3 years (range 29.1–88.5). The clinical symptoms were splenomegaly in 21.2%, hyperviscosity in 15.9%, lymphadenopathy in 15.9%, and polyneuropathy in 11.2%. 12.9% had a previous phase of IgM-MGUS. Pts from PP were older (median 65.3 vs. 62.5, p=0.01). Mean hemoglobine level at diagnosis was lower in pts from UH (11.4 vs. 12.2, p=0.04). There was no significant difference in mean platelet count, IgM and ß2-microglobuline level at diagnosis. 54% of pts from PP have received treatment during the observation time, as compared to 78.1% of the UH (p<0.001). The most common first line treatment protocols of PP were Chlorambucil (17/40, 42.5%), Bendamustin (17.5%) and Rituximab(R)-Bendamustin (17.5%). The UH most commonly administered R-Pentostatin-Cyclophosphamide (28%), Chlorambucil (17.3%) and COP (16%). 35% of the treated pts of PP have received R, as compared to 62.6% of the pts of the UH (p<0.001). 60% of the treated pts of PP have received Bendamustin, as compared to 8% of the pts of the UH (p<0.001). The time to first treatment was significantly shorter in pts from the UH (median 13.7 mo.) as compared to PP (52.9 mo.) (p=0.05). Median overall survival of all pts was 25.0 yrs and did not differ between PP and UH. Conclusion: Pts with WM treated in PP were older and had higher initial hemoglobin levels as compared to pts from the UH. Treatment differs significantly between PP and UH. Time to first treatment was significantly shorter in pts from UH. Overall survival was excellent, and better than reported previously. Disclosures: Hensel: Roche: Honoraria, Research Funding; Mundipharma: Research Funding.

Clinical Significance of Genetic Mutations of CD79B, CARD11, MYD88, and EZH2 Genes in Diffuse Large B-Cell Lymphoma Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2633-2633
Author(s):  
Chisako Iriyama ◽  
Akihiro Tomita ◽  
Takashi Tokunaga ◽  
Keisuke Sugiyama ◽  
Junji Hiraga ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Research Funding ◽  
Clinical Symptoms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Mutations ◽  
Overall Survival Rate ◽  
Large B Cell Lymphoma ◽  
The Relationship

Abstract Abstract 2633 Background: Recently, single nucleotide polymorphism array and next generation DNA sequencing techniques have been used to identify several genetic mutations in diffuse large B-cell lymphoma (DLBCL). The mutations seem to be localized in the B-cell receptor and NF-k B signaling pathway and histone- and DNA methylation-related enzymes. However, the relationship between the genetic mutations and the clinical features, such as outcome and disease progression, and pathological findings, has not yet been elucidated. Aims: To confirm frequency of genetic mutations in Japanese DLBCL patients, and to examine the relationship between genetic mutations and clinical and pathological features of the disease, including prognosis, responsiveness to chemotherapy with/without rituximab, and to examine the correlation between mutations and patient clinical symptoms. Methods: Genomic DNA was extracted from lymphoma cells harvested from 138 DLBCL patients enrolled in this study at Nagoya University Hospital. Genetic mutations in the coding regions of CD79B, CARD11, MYD88, and EZH2 were confirmed using pyrosequencing and direct DNA sequencing analyses. DLBCL subtype, germinal center B (GCB; 37 cases) or non-GCB cell (40 cases), were confirmed by immuno-pathological analysis. Overall survival rate was calculated by Kaplan-Meier analysis, and statistical differences were detected by the log-rank test. Results and Discussion: Mutations in CD79B leading to disruption of the immunoreceptor tyrosine-based activation motif (ITAM) were observed in 15 cases [10.5%; GCB, 2 cases (5.4%) and non-GCB, 4 cases (10.0%)], and mutations resulting in Y196 substitution, which is known to be a phosphorylation site critical for signal transduction, were confirmed in 13/15 cases (86.7%). Mutations in the coiled-coil (C-C) domain of CARD11 were detected in 4 cases [2.9%; GCB, 1 case (2.7%) and non-GCB, 1 case (2.5%)]. TIR (Toll/IL1 receptor) mutations in MYD88 were detected in 17 cases [12.3%; GCB, 3 cases (8.1%) and non-GCB, 6 cases (15%)], and Y265P substitution was confirmed in 14/17 cases (82%). Y641 substitution in EZH2 was detected in 9 cases [6.5%; GCB, 6 cases (16.2%) and non-GCB, 2 cases (5.0%)]. The frequency of EZH2 mutation was almost equivalent with previous reports, but the mutation frequencies of CD79B, CARD11, and MYD88 were much lower. Genetic mutations were confirmed in both CD79B and MYD88 in 6 cases (4.3%), while the frequency of CD79B and MYD88 mutations individually were 40% and 35.3%. Overall survival was compared between patients with or without each genetic mutation. Patients with CD79B and MYD88 mutations tended to have relatively poor outcomes, but the differences were not statistically significant (p=0.12 and 0.40, respectively). Patients with the EZH2 mutation showed relatively better outcomes, but the difference was not statistically significant (p=0.57). The overall survival rate of subjects with the CARD11 C-C mutation was significantly lower (p<0.0001), with the median overall survival of mutation(+) and (−) of 308.5 and 2950 days, respectively. Clinical records indicate that all cases with mutations were diagnosed as DLBCL at stages I (1 case), II (1 case), and IV (2 cases) and died due to disease progression within 1 year after the first diagnosis. Although we could not demonstrate statistically significant differences in overall survival for presence of CD79B, MYD88, and EZH2 mutations in this investigation, the tendencies observed here warrant further investigation with larger numbers of patients. Since prognosis was significantly poor in patients with the CARD11 C-C mutation, a more detailed extraction of their clinical symptoms is needed to confirm which phenomenon are related to the CARD11 C-C mutation. Disclosures: Naoe: Zenyaku-Kogyo: Research Funding; Novartis Pharma.: Honoraria, Speakers Bureau; Chugai Pharma.: Research Funding; Dainipponn-Sumitomo Pharma.: Research Funding; Kyowa-Hakko Kirin.: Research Funding; Otsuka Pharma.: Research Funding.

scholarly journals Excellent Outcome of Young Patients (18-60 years) with Favourable-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL) Treated with 4 Cycles CHOP Plus 6 Applications of Rituximab: Results of the 592 Patients of the Flyer Trial of the Dshnhl/GLA

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 781-781 ◽  
Author(s):  
Viola Poeschel ◽  
Gerhard Held ◽  
Marita Ziepert ◽  
Bettina Altmann ◽  
Mathias Witzens-Harig ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Standard Treatment ◽  
Young Patients ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Favourable Prognosis ◽  
Significant Difference ◽  
To Receive

Abstract Background: 6 cycles CHOP-like chemotherapy plus rituximab (6x R-CHOP) are the standard treatment for young patients with DLBCL. The MInT trial established a subgroup with favourable prognosis as defined as aaIPI=0 and no bulky disease [Pfreundschuh et al., Lancet Oncol 2006; 7: 379-391] with a 3-year EFS of 89%, PFS of 95% and OS of 98%. We hypothesized that 4 cycles of CHOP plus 6 applications of rituximab are non-inferior to the standard treatment of 6x R-CHOP in this population. Patients and Methods: 18 to 60 year-old patients, aaIPI =0 without bulky (≥7.5 cm) disease were randomized to receive 6x R-CHOP or 4x R-CHOP+2xR at 21-day cycles. Radiotherapy was not planned to be given except for prophylactic radiotherapy of the contralateral testis in patients with testicular lymphoma. The primary endpoint was progression free survival (PFS) with events defined as progressive disease, relapse or death. Assuming a 93% 3-years PFS for the 6x R-CHOP arm, it was planned to tolerate an impairment of 5.5% by reducing the number of courses to 4x R-CHOP+2xR to prove non-inferiority with a power of 80% and an alpha-error of 5% (one-sided). Results: Between 12/2005 and 10/2016, 592 patients were randomized in the international multi-center FLYER trial and 588 patients were evaluable for this final analysis. 295 patients were assigned to receive 6x R-CHOP and 293 were assigned to receive 4x R-CHOP+2xR. There were no relevant differences in demographics (median age: 48 years, 99% aaIPI=0, 1% aaIPI=1, 0.3% bulky disease), protocol adherence and toxicity between the two arms. PFS, EFS and OS after 4x R-CHOP+2xR were as good as after 6x R-CHOP. After 66 months median observation, the 3-year PFS rate of the patients receiving 4x R-CHOP+2xR was 96% vs. 94% of patients receiving 6x R-CHOP (p=0.760). The lower limit of the 95% CI of the difference between treatment arms was 0% and excludes -5.5% demonstrating the non-inferiority. The 3-year EFS was identical (89%) in both treatment arms. The 3-years OS was 99% in patients receiving 4x R-CHOP+2xR and 98% in patients receiving 6x R-CHOP. In a multivariable analysis adjusting for strata (stage and E-involvement), the hazard ratio of 4x R-CHOP+2xR compared to 6x R-CHOP was 1.0 (95% CI: 0.7-1.6; p=0.896) for EFS, 0.9 (95% CI: 0.5-1.6; p=0.797) for PFS, and 0.8 (95% CI: 0.4-1.9; p=0.671) for OS. With respect to relapse rate there was also no significant difference between the two treatment arms. 4% (95% CI 2-7%) of the patients in the 4x R-CHOP+2xR arm relapsed vs. 5% (95% CI 3-8%) of the patients in the 6x R-CHOP arm. 33% of relapses occurred in the first two years after study inclusion but continue to be seen with longer follow-up in both arms. Conclusion: In young patients with favourable prognosis DLBCL outcome after 4x R-CHOP+ 2xR is non-inferior compared to the previous standard 6x R-CHOP. Thus, chemotherapy can be spared without compromising prognosis in this population. Supported by Deutsche Krebshilfe Figure. Figure. Disclosures Poeschel: Roche: Other: Travel grants; Amgen: Other: Travel grants. Held:BMS: Consultancy, Other: Travel grants, Research Funding; Amgen: Research Funding; Roche: Consultancy, Other: Travel grants, Research Funding; MSD: Consultancy; Spectrum: Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Keller:Celgene: Research Funding; BMS: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; MSD: Consultancy. Schmidt:Gilead: Honoraria, Other: Travel Grants; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Stilgenbauer:Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmitz:Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Murawski:Takeda: Consultancy; Janssen: Other: Travel grants.

Aggressive Treatment in Glioblastoma: What Determines the Survival of Patients?

2020 ◽  
Author(s):  
Lei Yu ◽  
Guozhong Zhang ◽  
Songtao Qi
Keyword(s):  
Overall Survival ◽  
Malignant Gliomas ◽  
Epidemiological Studies ◽  
Control Cohort ◽  
Poor Overall Survival ◽  
Term Survival ◽  
Significant Difference ◽  
Positive Rate ◽  
Long Term Survivors

Abstract Background and Study Aims The exact reason of long-term survival in glioblastoma (GBM) patients has remained uncertain. Molecular parameters in addition to histology to define malignant gliomas are hoped to facilitate clinical, experimental, and epidemiological studies. Material and Methods A population of GBM patients with similar clinical characteristics (especially similar resectability) was reviewed to compare the molecular variables between poor (overall survival [OS] < 18 months, control cohort) and long-term survivors (overall survival > 36 months, OS-36 cohort). Results Long-term GBM survivors were younger. In the OS-36 cohort, the positive rate of isocitrate dehydrogenase (IDH) mutation was very low (7.69%, 3/39) and there was no statistical difference in OS between IDH mutant and wild-type patients. The results of 1p/19q codeletions are similar. Besides, there were no significant difference in MGMT promoter methylation, telomerase reverse transcriptase (TERT) promoter mutation, and TP53 mutations between OS-36 cohort and control cohort. Conclusions No distinct markers consistently have been identified in long-term survivors of GBM patients, and great importance should be attached to further understand the biological characteristics of the invasive glioma cells because of the nature of diffuse tumor permeation.

SP6.1.11 The Effect of the Enhanced Recovery Programme for Liver Surgery on Long Term Survival

2021 ◽  
Vol 108 (Supplement_7) ◽  
Author(s):  
Kalaiyarasi Arujunan ◽  
Abdulwarith Shugaba ◽  
Harmony Uwadiae ◽  
Joel Lambert ◽  
Georgios Sgourakis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Postoperative Complications ◽  
Liver Surgery ◽  
Patient Survival ◽  
Enhanced Recovery ◽  
Readmission Rates ◽  
Term Survival ◽  
Significant Difference

Abstract Aims The Enhanced Recovery Programme for Liver Surgery (ERPLS) has been shown to promote functional recovery and reduce hospital stay. However, its effect on long term survival has yet to be established. The aim of this study was to determine the effect of the ERPLS on 5-year patient survival. Methods This was a retrospective study of patients who underwent liver resection for colorectal liver metastasis (CRLM) between January 2011 and December 2016 at a regional hepatobiliary centre. The cohort comprised of 60 pre-ERPLS and 60 post-ERPLS patients. The primary outcome was 5-year patient survival. The secondary outcomes were length of stay (LOS), postoperative complications and 90-day readmission rates. Multivariate analysis was performed to identify independent predictors of overall survival. Results There was no significant difference in the age (p = 0.960), gender (p = 0.332) and type of resection (p = 0.198) between both groups. ERPLS was not an independent predictor for overall survival (Gehan Wilcoxon Test, p = 0.828). There was no significant difference in the LOS (p = 0.874) and 90-day readmission rates (p = 0.349). Major postoperative complications (&gt;3a Clavien-Dindo classification) were significantly less in the ERPLS group (p = 0.02). On multivariate analysis, positive resection margins and major postoperative complications were independent predictors for overall survival. Conclusions ERPLS does not seem to have an effect on long term patient survival. However, it appears to reduce the rate of major postoperative complications. LOS and 90-day readmission rates were not influenced by ERPLS.

Improved survival for patients with acute myelogenous leukemia.

1995 ◽  
Vol 13 (3) ◽  
pp. 560-569 ◽  
Author(s):  
A J Mitus ◽  
K B Miller ◽  
D P Schenkein ◽  
H F Ryan ◽  
S K Parsons ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Remission Induction ◽  
Term Survival ◽  
Free Survival ◽  
Significant Difference ◽  
Acute Myelogenous ◽  
To Receive

PURPOSE Despite improvement in chemotherapy and supportive care over the past two decades, overall survival for patients with acute myelogenous leukemia (AML) remains poor; only 25% to 30% of individuals with this disorder will be cured. In 1987, we initiated a prospective multiinstitution study designed to improve long-term survival in adults with AML. METHODS We modified the usual 7-day treatment scheme of daunorubicin and cytarabine with high-dose cytarabine (HiDAC) on days 8 through 10 (3 + 7 + 3). Allogeneic or autologous bone marrow transplantation (BMT) was offered to all patients who entered complete remission (CR) to decrease the rate of leukemic relapse. Data were analyzed by intention to treat. RESULTS CRs were achieved in 84 of 94 patients (89%; 95% confidence interval [CI], 83 to 95). Because of the high remission rate, factors previously thought to predict outcome, such as cytogenetics, WBC count, French-American-British (FAB) classification, sex, and age, were not useful prognostic variables. The overall survival rate for the entire cohort of patients from data of diagnosis is 55% at 5 years. Sixty percent of all patients who achieved a CR underwent marrow grafting. There was no significant difference in event-free survival (EFS) at 5 years comparing patients assigned to receive allogeneic BMT with patients assigned to receive autologous BMT (56% v 45%, P = .54). CONCLUSION The long-term disease-free survival observed in this study is excellent compared with historical data. This improvement in survival is probably due to the high rate of remission induction, as well as to the effective nature of the consolidation therapy.

Efficacy of a Brief, Cyclophosphamide-Intensive Regimen for Older Patients with Newly Diagnosed Burkitt's or Atypical Burkitt's Lymphoma/Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2685-2685
Author(s):  
Yvette L. Kasamon ◽  
Robert A. Brodsky ◽  
Michael J. Borowitz ◽  
Pamela A. Crilley ◽  
Richard F. Ambinder ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Time ◽  
Older Patients ◽  
Research Funding ◽  
Tumor Lysis Syndrome ◽  
B Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
High Dose ◽  
Newly Diagnosed

Abstract Abstract 2685 Poster Board II-661 Background: Although standard therapies cure most adolescents and young adults with Burkitt's lymphoma/leukemia (BL), older patients (pts) have an inferior prognosis with an estimated 1-year survival of 50%. The inferior outcome is attributable to both insufficient efficacy and excess toxicity. Cyclophosphamide (Cy) has long been recognized to be arguably the most active agent in BL. Prior work at our institution showed that high-dose Cy, equivalent to transplantation doses, could be given without stem cell rescue with minimal toxicity even in older pts. Patients and Methods: A phase II trial for pts age ≥ 30, based on intensive Cy and incorporating rituximab but no anthracycline, was developed with a primary endpoint of 1-year overall survival. Entry requirements included newly diagnosed BL or atypical BL; any performance status (PS); HIV negative; and no significant cardiac dysfunction. Renal failure, even if necessitating dialysis, was permitted if it was acute. Treatment consisted of 3 cycles, with successive cycles beginning on day 15 or when ANC was ≥ 500/μL. Cycles 1 and 2 consisted of Cy 1500 mg/m2 IV day 1; vincristine 1.4 mg/m2 (2 mg cap) day 1; prednisone 100 mg days 1-5; rituximab 375 mg/m2 IV days 1 and 8; methotrexate 3 g/m2 IV day 8 with leucovorin rescue; cytarabine 100 mg intrathecally days 1, 4, and 11; and filgrastim. Cycle 3 consisted of rituximab 375 mg/m2 IV day 1; high-dose Cy (50 mg/kg IV days 2, 3, 4, and 5) with uroprotection; filgrastim; and rituximab 375 mg/m2 IV weekly for 4 weeks once ANC was ≥ 1000/μL. Eligibility for cycle 3 included ECOG PS < 4; no disease progression or uncontrolled meningeal disease; not on dialysis; and transaminases ' 5X upper limit of normal. Results: A prespecified interim analysis of the first 12 of a planned 20 evaluable pts is presented. Diagnosis was BL in 8 and atypical BL/unclassifiable high-grade lymphoma with features intermediate between BL and diffuse large B-cell lymphoma in 4. Median age was 56 (range 34 – 75), 8/12 (67%) had Ann Arbor stage III/IV disease, and all were high-risk by Magrath's criteria. PS ranged from 0 to 4. Two pts received hemodialysis on presentation. For all pts, actuarial event-free survival and overall survival (Figure) are 66% and 75%, respectively, at both 1 year and 2 years after treatment initiation. Three pts died during cycle 1: tumor lysis syndrome on day 1, neutropenic sepsis on day 8, multiorgan failure on day 46 after respiratory arrest on day 20. All of the other 9 pts completed protocol therapy: 8 (89%) achieved anatomic CR/CRu as well as a complete metabolic response by PET, and are event-free at a median of 29 months (range < 1 – 44 months) after therapy completion. The remaining pt had residual marrow disease followed by progression and is in remission 1 year after myeloablative allogeneic BMT. Adverse events in these 9 pts included 7 neutropenic fevers; 1 non-neutropenic bacteremia; and 1 self-limited episode of pericarditis with rapid atrial fibrillation. Grade 3 peripheral neuropathy was limited to 2 pts. The planned dose intensity was achievable: median time to cycle 2 was 15 days (14 – 21), and median time from start of cycle 1 to start of cycle 3 was 31 days (28 – 35). Median time to neutrophil recovery after the last dose of Cy was 16 days (10 – 21); median time to platelets ≥ 20,000/μL, without transfusion in the preceding week, was 22 days (0 – 30). Early stopping criteria for response or all-cause mortality have not been met. Conclusion: A very short regimen based on intensive Cy without anthracycline produces a high rate of durable CR's in older, poorer-risk pts with BL or atypical BL. Disclosures: Kasamon: Genentech: Research Funding. Swinnen:Genentech: Consultancy, Research Funding; Enzon: Consultancy; Abbot: Consultancy, Research Funding.

Initial Results of the Phase I/II Panobidara Study of Panobinostat in Combination with Idarubicin and Cytarabine in Patients Aged 65 Years or Older with Newly Diagnosed Acute Myeloblastic Leukaemia (AML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1512-1512
Author(s):  
Enrique M Ocio ◽  
Pilar Herrera ◽  
Teresa Olave ◽  
Salut Brunet ◽  
Albert Oriol ◽  
...  
Keyword(s):  
Overall Survival ◽  
Elderly Patients ◽  
Phase I ◽  
Research Funding ◽  
Maintenance Phase ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Deacetylase Inhibitor

Abstract Abstract 1512 Introduction: Acute Myeloblastic Leukemia (AML) in elderly patients remains an unmet medical need with a long term survival rate inferior to 10% despite the use of novel drugs. Therefore, there is a need for new agents that could induce higher CR rates and, most importantly, that could prolong the relapse free survival (RFS) and the overall survival (OS) of these poor-prognosis patients. Agents targeting epigenetics such as the hypomethylating drug 5-Azacitidine, have emerged as a promising strategy for elderly patients with AML or MDS. A second group of drugs targeting the epigenome are deacetylase inhibitors. Panobinostat is a pan-deacetylase inhibitor, with clear in vitro activity in AML and which is synergistic with anthracyclines (Maiso et al. Leukemia 2009). Based on these data we designed a phase I/II trial of panobinostat in combination with idarubicine and cytarabine followed by panobinostat maintenance in newly diagnosed AML patients older than 65 years. Methods: The initial schema included one or two induction cycles with idarubicine (8 mg/m2 days 1–3) + cytarabine (100 mg/m2 days 1–7) followed by escalating doses of panobinostat three days per week, per 3 weeks starting at 20 mg. Patients achieving CR/CRi received a consolidation cycle with the same schema. Those patients remaining in CR/CRi started a maintenance phase with 40 mg oral panobinostat in monotherapy three days per week, for 3 weeks in 28-days cycles. This schedule was amended after the six first patients, to reduce the weeks of administration of panobinostat to two weeks in the cycles in combination and to every other week in the maintenance phase. Initially a dose-escalating phase I with the classical 3+3 schema was carried out to define the maximum tolerated dose (MTD) of panobinostat in this combination; and then a phase 2 expansion phase was started to determine the efficacy of this combination in terms of CR rate and RFS. Results: 21 patients have been included after the amendment. Median age was 71 (range 66–83). Median % blasts was 40 (20–93). 35% of patients had AML with dysplastic features while adverse cytogenetics were present in 24%. Two out of 6 evaluable patients in the first cohort developed DLTs with panobinostat 20 mg (G3 hyperbilirrubinaemia in both, and one of them also G3 oedema), accordingly the dose of panobinostat was reduced to 10 mg. No DLTs were observed at this dose level, so 10 mg panobinostat was defined as the MTD in this combination. Treatment was well tolerated in the intensive cycles with the toxicity proper of standard induction chemotherapy. The most common non-hematologic toxicities (occurring in ≥20% of patients) included: fever (90%), infections (62%), mucositis (52%), diarrhoea (62%), constipation (43%), vomiting (57%), skin rash (38%), hepatotoxicity (38%) and hypokalaemia (24%). Grade 3/4 AEs were fever, infection, diarrhoea and hepatotoxicity in 2 patients each (10%) and hypokalaemia in 5 (24%). The median duration of the aplasia was 32 days (range 26–51). Regarding the maintenance phase with panobinostat monotherapy, the most frequent AEs were gastrointestinal: diarrhoea (62%), vomiting (62%) or abdominal pain (25%); as well as asthenia (50%. One of them being G3) and hyporexia (25%). In terms of efficacy, 11 patients (52%) achieved CR plus 2 more (10%) achieving CR with incomplete blood recovery (CRi) (overall 62%). There were 2 deaths in induction (10%), one due to a tumoral lysis syndrome before starting panobinostat and the other secondary to a respiratory infection. From the remaining 6 patients, 2 achieved partial response (10%) and 4 showed refractory disease (19%). With a median follow up of 6 months (range 2–14), among the 11 patients that achieved CR, 10 of them remain in CR and only 1 has progressed (in the 9th maintenance cycle). Both patients that achieved CRi have progressed in the 2nd and 6thmaintenance cycles. The median overall survival for the whole population is 13 months (2.3–23.6), and has not been reached for patients achieving CR. Conclusion: To the best of our knowledge, this is the first report of the use of a histone deacetylase inhibitor with chemotherapy in elderly AML patients. This combination was shown to be safe at the MTD. Although preliminary results are encouraging, particularly for the potential benefit of the maintenance phase, longer follow up is needed to evaluate if panobinostat maintenance is able to prolong RFS and subsequently OS in this poor prognostic population. Disclosures: Ocio: Novartis: Consultancy, Research Funding. Off Label Use: Panobinostat in newly diagnosed AML. Aliseda:Novartis: Employment. Winiger:Novartis: Employment. Hardikar:Novartis: Employment. Mateos:Novartis: Consultancy. San-Miguel:Novartis: Consultancy, Research Funding.

Diffuse Large B-Cell Lymphoma (DLBCL) Patients Failing Second-Line R-DHAP Or R-ICE Chemotherapy Included In The Coral Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 764-764 ◽  
Author(s):  
Eric Van Den Neste ◽  
Christian Gisselbrecht ◽  
Norbert Schmitz ◽  
Nicolas Mounier ◽  
Devinder S Gill ◽  
...  
Keyword(s):  
Research Funding ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
New Drugs ◽  
High Dose ◽  
Second Line ◽  
Line Therapy ◽  
Significant Difference ◽  
Third Line Therapy ◽  
Third Line

Abstract Introduction and Methods Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is the standard of care for relapsing/refractory DLBCL. In the CORAL study, there was no difference between two randomized second line regimens (R-DHAP or R-ICE) and only half of the patients (pts) eventually underwent per protocol ASCT (Gisselbrecht et al, JCO 2010 & 2012). Because outcome data are limited in DLBCL pts failing second-line strategy, 145 pts included in the CORAL study who failed R-DHAP or R-ICE and could not proceed to scheduled ASCT were herein reviewed. Results Median age was 56y (range 20-67, 31% > 60y), M/F ratio 91/54, IPI 0-1 in 30%, 2-3 in 56%, and 4-5 in 14%. Third-line therapy consisted of ICE-type (19%), DHAP-type (19%), gemcitabine-containing (16%), CHOP-like (8%), dexaBEAM (8%), and miscellaneous (31%) regimens with or without rituximab according to centre policy. Overall response rate to third-line chemotherapy was 43%, with 21% complete response (CR), 8% CR unconfirmed (CRu), and 14% PR. CR/CRu and PR rates among pts treated with ICE-type, DHAP-type, gemcitabine-containing, or CHOP-like regimens were 23 and 23%, 35 and 8%, 9 and 4%, 25 and 25%, respectively. Among the 145 patients, 64 (44%) could eventually be transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS), calculated from time of second failure until death, was 5.9 months (95% CI 4.6-7.5; min: 0.0-max: 68.8 months; median follow-up: 32.8 months) and was not influenced by the type of third-line regimen (p=.49). OS was statistically different (p<.0001) according to IPI at CORAL failure: IPI 0-2: 11.1 months (1-y OS 42.9%), IPI > 2: 3.7 months (1-y OS 7.7%, HR 3.021). OS in pts achieving CR/CRu, PR, or no response after third-line regimen was 63.6 m (1-y OS 72.1%, p<.0001), 12.8 m (1-y OS 53.5%, p=.04), and 4.4 months (1-y OS 9.2%), respectively. Median OS of pts who could eventually be transplanted was 11.1 months (1-y OS 41.6%), as compared to a median OS of 5.0 months in those who were not transplanted (1-y OS 19.2%) with a HR of 2.182 (1.41-3.38, p<.0001, Figure 1). Median OS of pts transplanted in CR after third-line regimen was not reached as compared to those in PR (11.8 months) or those with no response (4.4 months, p<.0001). There was no statistically-significant difference in median OS between ASCT and alloSCT, taking into account the low numbers. In multivariate Cox analysis, IPI at relapse (HR 2.409) and transplantation (HR 0.381) independently predicted for OS. Conclusions Outcome of DLBCL pts failing second-line R-DHAP or R-ICE is overall poor. However, response to third-line therapy occurs, and 44% of the pts can be further transplanted. Long-term disease control can be observed, especially in pts achieving CR after third-line. This approach (salvage chemotherapy aiming at achieving response followed by transplantation) should then be encouraged in these patients, although there is obviously an urgent need for new drugs improving salvage efficacy. Disclosures: Gisselbrecht: Roche: Consultancy, Research Funding; Baxter: Research Funding; Chugai Pharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Radford:Roche: Consultancy. Shpilberg:Roche: Consultancy, Honoraria, Research Funding. Dührsen:Roche Pharma: Honoraria, Research Funding. Moskowitz:Genentech: Consultancy, Research Funding. Glass:Roche: Honoraria, Research Funding.

Autoimmune Cytopenia in Chronic Lymphocytic Leukemia: Effect on Outcome and Survival, a Population Based Analysis in British Columbia, Canada

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1945-1945 ◽  
Author(s):  
Alaa A Alzaki ◽  
Alina S Gerrie ◽  
Tanya L. Gillan ◽  
Steven Huang ◽  
Miriam Ahmed ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Population Based ◽  
Lymphocytic Leukemia ◽  
Time Interval ◽  
Poor Prognostic Factor ◽  
Significant Difference ◽  
Positive Direct ◽  
Time To First Treatment

Abstract Background: Among Chronic Lymphocytic Leukemia (CLL) patients (pts), 4-10% are diagnosed with autoimmune cytopenias (AC) at some point during the course of their disease. This is less common than cytopenias related to bone marrow infiltration (10-20%). Infiltrative cytopenias (IC) are clearly a poor prognostic factor. However, the effect of AC on survival and prognosis of CLL pts remains understudied. Objectives: To determine the prevalence of AC and IC among CLL pts and their effect on overall survival (OS) and time to first treatment (TTFT) compared to patients without cytopenia. Furthermore, the effect of different treatment modalities including chemotherapy and chemo-immunotherapy on the disease course was evaluated in patients with AC. Methods: A population-based retrospective analysis through an electronic search of pts within the Providence Health Care CLL database between 1978 and 2013 was carried out. The diagnostic criteria for autoimmune hemolytic anemia (AIHA) were positive direct antiglobulin test and laboratory evidence of hemolysis, for immune thrombocytopenia (ITP) the exclusion of other etiologies of thrombocytopenia and for pure red cell aplasia (PRCA) anemia with low reticulocyte count and bone marrow evidence of decreased erythropoiesis. Infiltrative cytopenia diagnosis was confirmed by bone marrow biopsy based on lymphocyte percentage and cellularity. Anemia was defined as hemoglobin <100 g/L. Thrombocytopenia was defined as platelets <100 x 109/L. Baseline features of pts with AC and IC were compared using Chi-squared analysis for categorical and the Kruskal-Wallis test for continuous variables. Overall survival was calculated from the date of initial treatment to the date of death from any cause. Time to first treatment (TTFT) was defined as the time interval between the date of diagnosis and date of first CLL treatment. Survival analysis was performed by the Kaplan–Meier method using IBM SPSS statistics for windows. Results: Among 754 pts with CLL, 80 (10.6%) developed cytopenias (anemia and thrombocytopenia). Of those, 50 (6.6%) had IC and 30 (4%) had AC. There was no significant difference between the 2 groups in terms of age, gender, hemoglobin, platelets, LDH, WBC and lymphocyte count at diagnosis. The time to development of cytopenias for the IC and AC groups was similar with median of 3 and 4 years (yrs) from diagnosis, respectively. Within the AC group 16 pts had AIHA, 8 had ITP, 5 had both (Evan's Syndrome) and 1 had PRCA. The median OS was 12.2 yrs (5.9–18.3) and 13 yrs (1.6-24.3) for IC and AC, respectively (p=0.260). However, when compared to CLL pts without cytopenias (median not reached), the AC group had worse OS (p< 0.005) (Fig 1). For the IC and AC groups, the median TTFT was 6.5 yrs (4.5-8.5) and 8.2 yrs (4.1–12.3), respectively (p=0.191). For the CLL pts without cytopenias TTFT was 8.1 yrs (2-12.2), similar to the AC group (p=0.88) (Fig 2). For AC pts, the OS was not significantly different based on treatment received: alkylator based therapy vs. chemo-immunotherapy (p= 0.885). The effect of concomitant hypo-gammaglobulinemia on OS and treatment outcome was studied.Of the 30 pts with AC, 26 had a serum protein electrophoresis done. Of those, 10 (38.5%) had normal results and 16 (61.5%) had low gammaglobulin levels (IgG< 6 g/L); the mean OS was 18.1 yrs and 15.7 yrs respectively (median not reached), (P=0.433). Conclusion: The prognosis of pts with autoimmune and infiltrative cytopenias was similar.However, CLL pts with AC had worse OS compared to those without cytopenias. There was no significant difference in TTFT between AC and IC or when compared to CLL pts without cytopenias. For the AC group, neither treatment with chemotherapy vs. chemo-immunotherapy nor having concomitant hypo-gammaglobulinemia had an effect on outcome. To our knowledge, there are limited population based studies addressing the importance of determining the etiology of cytopenias in CLL pts and the effect of AC on survival. CLL immune complications need to be studied further especially in the context of novel agents and their effects on immune reconstitution. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

ΝFΚΒΙΕ Deletions: A Novel Marker of Clinical Aggressiveness in Primary Mediastinal B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 609-609
Author(s):  
Daniel Noerenberg* ◽  
Larry Mansouri* ◽  
Emma Young ◽  
Frick Mareike ◽  
Maysaa Abdulla ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
High Frequency ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Gene Mutations ◽  
B Cell Lymphoma ◽  
Mutation Status ◽  
Lymphoid Malignancies ◽  
Ann Arbor

Abstract Deregulated NF-κB signaling is a hallmark of most, if not all, lymphoid malignancies, and recurrent gene mutations in both the canonical and non-canonical NF-κB pathway are known to lead to NF-κB activation. However, the full compendium of NF-κB gene mutations in lymphoid malignancies remains to be elucidated. Recently, we reported a 4-bp truncating mutation in the NFKBIE gene, which encodes IκBε, a negative regulator of NF-κB, in patients with chronic lymphocytic leukemia (CLL). The NFKBIE deletion was enriched in clinically aggressive CLL patients (7-8%) and associated with a worse clinical outcome. At the functional level, NFKBIE-deleted CLL showed reduced IκBε levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65, compared to wildtype patients. Preliminary data has indicated an increased frequency of NFKBIE aberrations in other lymphoid malignancies as well. To explore this further, we screened for NFKBIE deletions in a large cohort of patients diagnosed with a range of different lymphoid neoplasms. Overall, NFKBIE deletions were identified in 76 of 1414 patients (5.4%). While NFKBIE deletions were relatively infrequent in patients diagnosed with follicular lymphoma (3/225, 1.3%), splenic marginal zone lymphoma (3/175, 1.7%), and T-cell acute lymphoblastic leukemia (1/94, 1.1%), moderate frequencies were observed among diffuse large B-cell lymphoma (18/521, 3.5%), mantle cell lymphoma (8/189, 4.2%), and primary CNS lymphoma (1/34, 2.9%) patients. In contrast, a remarkably high frequency of NFKBIE deletions (41/176 cases, 23%) was observed among primary mediastinal B-cell lymphoma (PMBL) patients. Noteworthy, the prevalence of NFKBIE-deleted PMBL cases was similar in the different contributing centers. All PMBL patients in the present series received a CHOP based treatment regime; in ~75% of cases rituximab was added and ~25% were treated with dose intensified schemes. For the latter, the vast majority of patients received CHOEP, while individual cases were treated with MegaCHOEP, DA-EPOCH or ACVBP. Regarding clinicobiological associations, there were no significant differences between NFKBIE-deleted and wildtype PMBL patients with respect to age, sex, Ann Arbor stage, IPI risk-groups, extranodal or bone marrow involvement, bulky disease, and LDH elevation. However, NFKBIE-deleted patients were more likely to be refractory to primary chemotherapy (31% vs. 3%, P=.001) and had a shorter overall survival compared to wildtype patients (5-year overall survival: 63% vs 84%, P=.013). In multivariate analysis (including age, gender, Ann Arbor stage, IPI, and NFKBIE mutation status), NFKBIE mutation status (95% CI: 1.23-10.61; HR: 3.61; P=0.020) remained an independent factor for poor prognosis. In summary, we document NFKBIE deletions as a common genetic event across B-cell malignancies, albeit at varying frequencies. The high frequency of NFKBIE deletions in PMBL alludes to the critical role of this aberration in the pathophysiology of the disease. NFKBIE deletions were associated witha worse clinical outcome, hence potentially representing a novel poor-prognostic marker in PMBL. *Contributed equally as first authors. **Contributed equally as senior authors. Disclosures Stamatopoulos: Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding.

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