Rituximab Resistant Follicular Lymphoma: Predictors of Rituximab Resistance, Incidence of Transformation and Prognosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4981-4981 ◽  
Author(s):  
Lee Mozessohn ◽  
Matthew Cheung ◽  
Michael Crump ◽  
Rena Buckstein ◽  
Neil L Berinstein ◽  
...  
Keyword(s):  
Partial Response ◽  
Follicular Lymphoma ◽  
Disease Progression ◽  
Board Of Directors ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Previous Treatment ◽  
Primary Therapy ◽  
Advisory Committees

Abstract Abstract 4981 Follicular lymphoma (FL) is an indolent lymphoma characterized by slow growth, initial response to treatment with inevitable relapse. Recent trials have demonstrated improved progression free survival (PFS) with rituximab-containing induction, maintenance rituximab (MR) or both. However, a small subset of patients (pts) will show disease progression during the induction or maintenance phase. We evaluated rituximab resistance (RR) including incidence, predictors, rate of transformation and prognosis for pts demonstrating RR. We defined RR as disease progression during induction, maintenance or within 6 months of last dose of rituximab. We retrospectively identified pts who received rituximab for symptomatic FL from July 2006 to April 2010 at 2 regional cancer centres. Those with a diagnosis of FL grades 1, 2 or 3a with first exposure to rituximab (induction, maintenance or both) were included. Exclusion criteria included FL grade 3b and previous rituximab exposure. Progression was ascertained from clinical notes or radiological investigation as per IWG Criteria (1999). Transformation was defined by confirmatory biopsy and clinical suspicion of transformation was also recorded (nodal growth, rapid rise in LDH or new B symptoms). PFS and overall survival (OS) were measured from initiation of rituximab induction. Log-rank statistics were used to identify univariate predictors for RR and Cox regression for multivariate analysis with outcome as time to early progression (RR). Of the pts screened, 132 met inclusion criteria (112 pts receiving primary therapy, 20 for ≥ 2nd line therapy); 22 pts (16.7%) demonstrated RR. Incidence of RR was similar for pts receiving primary therapy (17.0%). Pt characteristics for rituximab sensitive (RS) and RR groups are shown in Table 1. From induction, median follow-up was 33 months (range 9 to 61 months). In univariate analysis, high risk FLIPI score at induction was predictive of RR (p = 0.002). Partial response to induction (p = 0.082) trended to significance. Other factors not predictive of RR included: age, gender, high grade histology (grade 3a), previous chemotherapy received, time from diagnosis to induction therapy and anthracycline-based induction. A Cox regression model was constructed with FLIPI score and anthracycline-based induction as covariates. FLIPI score was independently and significantly predictive of RR (HR 2.43; 95% CI, 1.4 to 4.1; p = 0.001). Of the 22 pts who were RR, 18 (81.8%) required subsequent chemotherapy with only 9 achieving at least a partial response. Ten pts (45.5%) required more than 1 line of chemotherapy post-progression with a median time to next line of therapy of 9 months (95% CI, 2.9 to 15.1; see figure). Among the RR pts, 5 (22.7%) showed evidence of transformation on biopsy at initial resistance and an additional 3 (13.6%) were clinically suspected. Within 12 months of resistance, a further 3 pts in the RR group demonstrated biopsy-proven transformation. Overall, 10 pts (45.5%) transformed (biopsy-proven) with no transformation in the RS group. During follow-up, 9 deaths occurred, all in those with RR, 5 following biopsy-proven transformation. The median PFS and OS in the RR group were 17 months and 47 months, respectively. Table 1 Characteristics RS (n = 110) RR (n = 22) Age (MEAN) 58.9 58.9 Gender (females) 43.6% 40.9% High histological grade (3a) 8.4% 9.1% Previous treatment (yes) 15.5% 13.6% Alkylator 11.8% 13.6% Number of lines of previous treatment >1 4.5% 4.5% Mean time from diagnosis to induction (months) 30.3 28.1 Induction chemo R-CVP based 78.2% 86.4% R-CHOP based 18.2% 9.1% Other 3.6% 4.5% Response to induction PR 77.3% 72.7% CRu 12.7% 0% CR 10.0% 4.5% SD/PD 0% 22.7% FLIPI score at induction Low (0, 1, 2) 57.8% 18.2% Intermediate (3) 26.6% 40.9% High (4 or 5) 15.6% 40.9% Stage 3 or 4 88.2% 100% High tumor burden at diagnosis (GELF criteria) 43.6% 40.9% We demonstrated that the incidence of rituximab resistance in FL on first exposure to rituximab in our population was 16.7%. FLIPI score was predictive for RR and was independent of anthracycline-based induction regimens. Pts with RR had a high rate of histologic transformation (36.3% within 12 months post RR) and a shorter PFS/OS with a poor response to next therapy. Biopsies to confirm transformation should be performed in all pts demonstrating RR, and new therapies are needed for this group of pts. Disclosures: Crump: Ortho Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Honoraria; Ortho Biotech: Honoraria; Roche: Honoraria.

scholarly journals Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5263-5263
Author(s):  
Karin Hohloch ◽  
Christine Windemuth-Kieselbach ◽  
Pier Luigi Zinzani ◽  
Roberto E. Cacchione ◽  
Wojciech Jurczak ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Primary Therapy ◽  
First Line ◽  
Advisory Committees ◽  
Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

Final Analysis of a Randomized Comparison of ABVD Chemotherapy with a Strategy That Includes Radiation Therapy (RT) in Patients with Limited-Stage Hodgkin Lymphoma (HL): NCIC CTG/ECOG HD.6

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 590-590 ◽  
Author(s):  
Ralph M. Meyer ◽  
Mary Gospodarowicz ◽  
Joseph M. Connors ◽  
Robert G Pearcey ◽  
Woodrow A Wells ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Final Analysis ◽  
Primary Analysis ◽  
Advisory Committees ◽  
Limited Stage ◽  
Risk Patients ◽  
Single Modality

Abstract Abstract 590FN2 Background: The NCIC CTG / ECOG HD.6 trial is based on the hypothesis that for patients with limited-stage HL, treatment with single-modality ABVD provides comparable disease control, is associated with a reduced incidence of deaths due to late treatment effects and thus might improve long-term survival in comparison with treatment that includes extended-field RT. In this randomized controlled phase III trial, our primary objective was to compare the 12-yr overall survivals (OS) of limited-stage HL patients treated with ABVD alone with those receiving therapy that includes RT. Secondary outcomes include freedom from disease progression (FFDP), in which those dying prior to disease progression are censored, and event-free survival (EFS), in which the first of disease progression or death is considered an event. In 2005, we published 5-yr outcomes (median follow-up 4.2 yrs [Meyer, J Clin Oncol]). We now report results of the final analysis. Methods: Eligible patients had non-bulky clinical stage I-IIA HL; patients with subdiaphragmatic disease were eligible if disease was confined to the iliac, inguinal and/or femoral regions. Prior to randomization, patients were stratified into low and high-risk categories; low-risk patients had all of lymphocyte predominant or nodular sclerosis histology, age < 40 yrs, ESR < 50, and involvement of 3 or fewer disease-site regions; all others were high-risk. Patients randomized to therapy that includes RT received single-modality subtotal nodal irradiation (STNI) if low-risk and combined-modality ABVD (2 cycles) plus STNI if high-risk. All patients randomized to the experimental arm received single-modality ABVD (4 cycles); those not demonstrating a complete remission with restaging after 2 cycles received 6 cycles. Between March 1994 and April 2002, 405 patients were entered; 399 were eligible and included in the primary analysis (modified intent–to-treat [ITT]). The clinical cut-off date for follow-up was 2010/DEC/31 and the database was locked on 2011/JUL/15. All P-values are 2-sided. Results: The median duration of follow-up is 11.3 yrs. The OS was superior in patients randomized to ABVD (P=.04; HR=0.5; 12-yr estimates 94% vs. 87%). In comparison with patients randomized to therapy that includes RT, FFDP trended to being inferior in patients randomized to ABVD (P=.07; HR=1.82; 12-yr estimates 88% vs. 92%); no differences in EFS were detected (P=.5; HR=0.87; 12-yr estimates 86% vs. 80%). Sensitivity analyses included a true ITT evaluating all randomized patients and adding data obtained between the clinical cut-off and data-lock dates; results were robust and yielded similar findings. Causes of death in ABVD vs. RT-arm patients (N = 12 vs. 24) included HL or early treatment complication (6 vs. 4), second cancers (4 vs. 9), and other (2 vs. 11). Analysis of high-risk patients allocated to ABVD (N=137) vs. ABVD+STNI (N=139) showed similar respective results to the primary analysis: in comparison with those randomized to RT, OS was superior in the ABVD arm (12-yr estimates 92% vs. 81%; HR=.47; P=.04), FFDP was inferior (12-yr estimates 87% vs. 94%; HR=3.03; P=.01) and no differences in EFS were detected (12-yr estimates 84% vs. 78%; HR=.87; P=.6). Late-effects trended to being less frequent in ABVD patients, including second cancers (6.1% vs. 10.8%) and cardiac events (9.7% vs. 14.8%). Conclusions: We conclude that in patients with limited-stage HL, ABVD improves OS as compared with treatment that includes STNI, including combined modality therapy, because it is associated with fewer deaths from causes other than HL. The HD.6 trial hypothesis was thus confirmed. With respect to modern RT approaches, the implications of our results are: i) at 12 years, 88% of patients are disease-free and more than 90% are alive when initially treated with ABVD alone; ii) limitations exist in using FFDP as a proxy measure for OS when late treatment effects may occur; and, iii) when treatment strategies have competing risks, long-term follow-up provides crucial insights into the interpretations of best therapy. Disclosures: Connors: Seattle Genetics: Consultancy, Research Funding. Horning:Genentech: Employment, Equity Ownership. Crump:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy In Relapsed Or Refractory Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1955-1955 ◽  
Author(s):  
Tomer M Mark ◽  
Angelique Boyer ◽  
Adriana C Rossi ◽  
Dennis Kwon ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Response Analysis ◽  
Muscular Weakness ◽  
Advisory Committees ◽  
Disease Response ◽  
Grade 3

Abstract Background Pomalidomide is a distinct IMiD® immunomodulatory agent with activity in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have previously reported that the addition of clarithromycin enhances the anti-myeloma activity of pomalidomide+dexamethasone (Pom/Dex) in the treatment of RRMM (Mark et al, ASH 2012). We now report updated results with extended follow up from a phase 2 trial of large group of patients treated with ClaPd in RRMM. Methods One hundred nineteen patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPd. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPd is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1-21, and dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results One hundred fourteen patients had completed at least 1 cycle of ClaPd and were eligible for disease response analysis at data cut-off. All patients were included in the safety analysis. Patients had undergone a median of 5 (range 3-15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide+bortezomib) refractory were 85%, 79%, and 68% respectively. The median number of ClaPd cycles received was 7 (range 1-34). Overall response rate (ORR, ≥PR, entire cohort/double-refractory subgroup) was 61.4/56.4% [stringent complete remission (sCR): 4.4/4%, complete response (CR): 0.9/1.3%, very good partial response (VGPR): 14.9/11.5%, partial response (PR): 41.2/38.5%, minimal response (MR): 7/9%, stable disease (SD): 21.9/21.8%, progressive disease (PD): 9.6/12.8%, ³VGPR rate of 20.2/16.7%]. Clinical benefit (³ MR) was achieved in 68.4/65.4%. Median time to PR and maximum response was 1 (range 1-7) and 2 (range 1-18) cycles, respectively. After a mean follow up time of 11.9 months, 40 patients (34%) remain free from progression, with a median progression free survival of 8.1 months (95% CI: 5.1, 9.8). Median duration of response (DOR) was 9.3 months (95% CI: 7.2,16.1). Median overall survival (OS) has not been reached with 68 patients (57%) alive at last follow-up. Median PFS, DOR, OS were not significantly different in the double-refractory subgroup at 6.3 (CI 4.7, 8.7; p = 0.21), 8.6 (CI 6.5, 16.1; p = 0.87), and 16.8 months (CI 12.4, 28.7; p = 0.11) respectively. The most common (³% grade 3 and 4 toxicities were: neutropenia (49%), thrombocytopenia (39%), anemia (27%), pneumonia (10%), fatigue 8%, and muscular weakness 7%. Febrile neutropenia was uncommon at 2%. There were 6 cases of lower extremity venous thrombosis (5%, 1 grade 1, 4 grade 2, 1 grade 3) and no instances of pulmonary embolism. Mild peripheral neuropathy was present in 32% (19% grade 1, 13% grade 2), 0% grade 3 or 4). Grade 2 congestive heart failure, due to dexamethasone, emerged in 1 subject (0.8%). Four patients (3.3%) withdrew due to treatment related toxicity (1 with Grade 3 muscular weakness, 2 due to Grade 3 fatigue, 1 grade 4 neutropenic sepsis). There was no treatment related mortality. Conclusions ClaPd is a highly effective and tolerable regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPd is rapid and sustained at > 8 months in the majority of subjects. The presence of double refractory disease did not significantly impact clinical outcomes. The ORR and PFS compare favorably and toxicity profile is similar to other published reports of Pom/Dex. Disclosures: Mark: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1992-1992 ◽  
Author(s):  
Eugen Tausch ◽  
Christina Galler ◽  
Richard Schlenk ◽  
Peter Hillmen ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Gene Mutations ◽  
Phase Iii ◽  
Response To Treatment ◽  
Prognostic Impact ◽  
Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2000-2000
Author(s):  
Hagop Kantarjian ◽  
Pierre Fenaux ◽  
Mikkael A. Sekeres ◽  
Jeffrey Szer ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Controlled Study ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: Thrombocytopenia occurs in ~50% of patients with low/int-1 risk myelodysplastic syndrome (MDS) and is associated with reduced survival. In a placebo (PBO)-controlled study, 250 patients with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events [hazard ratio (HR) romiplostim vs PBO 0.83, 95% CI: 0.66−1.05, P = 0.13] and platelet transfusions (relative risk 0.77, 95% CI: 0.66−0.88, P<0.001) and increased IWG hematologic improvement platelets (HI-P) incidence (odds ratio 15.6, 95% CI: 4.7−51.8, P<0.001). Peripheral blast count increases >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%) and resolved after discontinuation in most cases. In February 2011, the DMC recommended that treatment with study drug be discontinued as the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML, and that transient increases in blast cell counts might put patients at risk for diagnosis of and treatment for AML. Patients were moved into long-term follow-up (LTFU). Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was 6.0% (N = 10) for romiplostim and 4.9% for PBO (N = 4); HR 1.20 (95% CI: 0.38−3.84). This report provides final 5-year LTFU data. Methods: Eligible patients were receiving only supportive care and had IPSS low/int-1 risk MDS and platelets 1) ≤20 × 109/L or 2) ≤50 × 109/L with a history of bleeding. Disease progression to AML was defined as 1) ≥20% blasts in bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim; 2) pathology consistent with leukemia; or 3) antileukemic treatment. Results are presented by treatment group. Results: At baseline, median (Q1, Q3) age was 70 (61, 77) years, the majority (59%) of patients were male; 27.6% were IPSS low risk and 72.4% were int-1 risk. WHO classifications were RCMD: 67.6%, RAEB-1: 13.2%, MDS-U: 11.2%, RA: 4.4%, RCMD-RS: 2.4%, RARS: 0.8%, and RAEB-2: 0.4%. Of 250 patients in the study, 210 entered LTFU and 66 completed the 5 years of LTFU; median (Q1, Q3) follow-up was 27.5 (10.8, 58.7) months. Reasons for discontinuation (death, lost to follow-up, and consent withdrawal) during LTFU were similar in both groups. During the active study period and LTFU, death was reported in 93 (55.7%) patients in the romiplostim group and 45 (54.2%) patients in the PBO group (HR romiplostim vs PBO 1.03, 95% CI: 0.72−1.47) (Figure); mortality rates were greater in those with IPSS int-1 vs low risk for both groups (Table). AML was reported in 20 (11.9%) patients in the romiplostim group and 9 (11.0%) patients in the PBO group (HR 1.06, 95% CI: 0.48−2.33). The proportions of patients who either died or developed AML were 56.9% (N = 95) in the romiplostim group and 55.4% (N = 46) in the PBO group (HR for AML-free survival 1.04, 95% CI: 0.73−1.48) (Figure). Nearly half (N = 14, 48%) of the 29 AML cases occurred in patients who were RAEB-1 at screening (none RAEB-2), and 6 cases were diagnosed because of anti-AML treatment use alone (Table). In LTFU, patient-reported use of MDS therapy (eg, azacitidine or cyclosporine) was 42.8% (N = 59, 95% CI: 34.4%−51.5%) in the romiplostim group and 31.4% (N = 22, 95% CI: 20.9%−43.6%) in the PBO group. AML therapy (eg, chemotherapy) was used in 14 (10.2%) patients in the romiplostim group and 7 (10.0%) patients in the PBO group. Conclusions: Following the decision in 2011 to stop study drug secondary to increased AML rates at that time and transient blasts increases, final 5-year LTFU HRs (romiplostim vs placebo) for death or progression to AML, respectively, are 1.03 (95% CI: 0.72−1.47) and 1.06 (95% CI: 0.48−2.33). In conclusion, romiplostim reduced bleeding events and platelet transfusions, with no increase in AML incidence or impact on survival. Disclosures Kantarjian: Amgen Inc.: Research Funding. Fenaux:Amgen Inc.: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kuendgen:Celgene: Research Funding. Gaidano:Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiktor-Jedrzejczak:Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy, Research Funding; BMS: Research Funding; Sandoz: Consultancy; Amgen Inc.: Research Funding. Carpenter:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3180-3180
Author(s):  
Felix Lopez-Cadenas ◽  
Blanca Xicoy ◽  
Silvia Rojas P ◽  
Kaivers Jennifer ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Rank Test ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

scholarly journals CAR T Therapy Referral for Diffuse Large B Cell Lymphoma (DLBCL) By U.S. Community Hematology/Oncology (cH/O) Practices: Perceptions and Patterns

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4977-4977
Author(s):  
David L Porter ◽  
Andrew J Klink ◽  
Alexandrina Balanean ◽  
Lindsay McAllister ◽  
Bruce A. Feinberg
Keyword(s):  
B Cell ◽  
Disease Progression ◽  
Board Of Directors ◽  
Patient Choice ◽  
Treatment Center ◽  
Advisory Committees ◽  
Rapid Disease Progression ◽  
Physician Perceptions ◽  
Car T

Abstract Introduction Chimeric antigen receptor T-cell (CAR T) therapy has resulted in a treatment paradigm shift for certain hematologic malignancies, with United States Food and Drug Administration approval of several products for patients with relapsed/refractory (RR) aggressive B cell lymphomas (BCL). Although most BCL patients are initially treated by cH/O physicians, current delivery of CAR T is limited to major academic centers. Consequently, there is a dearth of reporting on the complex aspects of cH/O involvement before and after CAR T therapy administration, which complicates determination of the magnitude of potential benefits. To appropriately incorporate this therapeutic option, and optimize patient care, communication and cooperation between cH/O and the CAR T center is critical; at a minimum, the referring cH/O's access to all aspects of the CAR T therapy continuum is paramount. To that end, this study surveyed cH/O physicians to determine: 1) whether adequate data were recorded and available to the cH/O; 2) timing of referral, leukapheresis, and CAR T infusion; 3) treatment prior to CAR T referral, and 4) physician perceptions on patient eligibility, barriers to access, and noncompliance. Methods This retrospective, observational, multicenter chart review assessed adult patients with RR DLBCL who received CAR T therapy in 2019. Patients with ≥6 months of post-CAR T therapy administration follow-up were identified by cH/O physicians participating in the Cardinal Health Oncology Provider Extended Network (OPEN). cH/O physicians provided their perceptions and experience with CAR T therapy via survey and abstracted patient data using electronic case report forms. Patient demographic/clinical/treatment characteristics and physician perceptions were summarized descriptively. Results Surveyed Perceptions: Top barriers to CAR T referral: patient choice (39%), location of CAR T center (31%), and preference for other therapy (31%); 39% reported no specific barriers. Rapid disease progression (69%) was the main reason patients would not undergo CAR T therapy after referral, followed by patient ineligibility (62%), patient choice (62%), and insurance coverage/patient cost (46%). Chart Abstraction: Data on 65 RR DLBCL patients were collected from 13 cH/O practices in all 4 U.S. regions (Table). Median duration of follow-up from CAR T therapy referral was 15 months. Median age at RR DLBCL diagnosis was 60 years, and most patients were male (63%) and White (79%). Most patients (92%) received anti-CD20 monoclonal antibody (mAb) + CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) as 1L therapy. At referral, 80% of patients (48/60) had lactate dehydrogenase levels above the upper limit of normal. Prior to CAR T infusion, all patients were reported to receive lymphodepletion treatment with fludarabine + cyclophosphamide. Median intervals among patients with and without disease progression, respectively, were: 9 weeks (8 vs 10) from CAR T referral to CAR T infusion, which comprised 5 weeks (4 vs 6) from CAR T referral to leukapheresis and 4 weeks (both groups) from leukapheresis to CAR T infusion. Conclusions The cH/O physicians' perceived barriers to CAR T therapy for their patients appear to conflict with the patient data; 69% thought that rapid disease progression precluded CAR T therapy but the reported 9-week interval from referral to CAR T infusion suggests reasonably timely intervention. This highlights the critical need for early referral with a commitment to prompt patient evaluation by the treatment center. The cH/O physician is vital for CAR T referrals and treatment decisions, and the recent increasing access to patients via telemedicine may help better integrate the cH/O, the patient, and the treatment center to promote access of patients to CAR T cell therapies, particularly when limited other options are available. Figure 1 Figure 1. Disclosures Porter: DeCart: Membership on an entity's Board of Directors or advisory committees; American Society for Transplantation and Cellular Therapy: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Klink: Cardinal Health: Current Employment, Current holder of stock options in a privately-held company. Balanean: Cardinal Health: Current Employment; Georgia State University: Other: former student and employee. McAllister: Cardinal Health: Current Employment. Feinberg: Cardinal Health: Current Employment.

scholarly journals Tracking Daratumumab Clearance Using Mass Spectrometric Approaches: Implications on M Protein Monitoring and Reusing Daratumumab

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2707-2707
Author(s):  
Nadine Abdallah ◽  
David L Murray ◽  
Angela Dispenzieri ◽  
Prashant Kapoor ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Research Funding ◽  
Univariate Analysis ◽  
M Protein ◽  
Urine Protein ◽  
Advisory Committees ◽  
Plasma Cell Disorders

Abstract Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein &lt;0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR &lt;60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs &gt;2weeks) (RR: 1.0, P=0.97), treatment duration (&lt;200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

scholarly journals Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4457-4457 ◽  
Author(s):  
Franck Morschhauser ◽  
Ian Flinn ◽  
Ranjana H Advani ◽  
Catherine S. Diefenbach ◽  
Kathryn Kolibaba ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Grade 5 ◽  
Grade 3

Abstract Background: Previously reported results from an ongoing study of polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV), antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in combination with rituximab (R) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Here we report updated results of ADC + R at the RP2D of 2.4 mg/kg and initial results of PoV + R in r/r FL at the PoV dose of 1.8 mg/kg. Methods: Pts were randomized to receive PoV or PiV + R (ADC 2.4 mg/kg + R 375 mg/m2). In a separate non-randomized cohort (Cohort C), r/r FL pts were treated with PoV (1.8 mg/kg) + R. ADC + R was given every 21 days. Tumor assessments were performed every 3 months. Results: As of 21 February 2014, 59 pts received PoV + R (39 DLBCL; 20 FL), 63 PiV + R (42 DLBCL; 21 FL); 20 r/r FL pts were treated in Cohort C. Median time of follow-up was 10 mo. for PoV + R, 9 mo. for PiV + R, and 5 mo. for Cohort C. Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced among the randomized treatment (tx) arms, median prior therapies in Cohort C was 2 (1-13); overall 44% were R refractory. Median tx cycles in DLBCL: 6 PoV (range 1-16) and 7 PiV (1-15); FL: 10 PoV (3-17), 7 PiV (1-14), and 6 Cohort C (2-10). Overall safety profiles of both regimens in the randomized arms receiving 2.4 mg/kg ADC were similar. The most common tx-emergent adverse events (AE) ≥25%: fatigue (55%), diarrhea (43%), nausea (37%), peripheral neuropathy (PN) (39%), neutropenia (27%), constipation (26%), sensory PN (25%), and decreased appetite (25%). Grade ≥ 3 AE >3%: neutropenia (24%), diarrhea (6%), dyspnea (5%), febrile neutropenia (4%), hyperglycemia (4%), fatigue (3%), and thrombocytopenia (3%). Serious AEs were reported in 43% and 36% of PiV and PoV treated pts, respectively. Discontinuation of study treatment for AE was reported in 49% and 41% of PiV and PoV treated pts, respectively. Thirty-five pts discontinued treatment due to PN with a median time to discontinuation of 5.6 mo. PN reversibility was observed following treatment interruptions and ADC dose modifications. Two of 9 Grade 5 AEs (sepsis, urosepsis) were attributed to CD22 ADC; no Grade 5 AEs were attributed to CD79b ADC. In Cohort C the most common tx-emergent AE ≥ 25%: fatigue (55%), nausea (45%), neutropenia (40%), sensory PN (30%), diarrhea (25%), constipation (25%) and pyrexia (25%). Grade ≥ 3 neutropenia was reported in 7 pts; no other Grade ≥ 3 AE was reported in >1 pt. Serious AE were reported in 5 pts. Two pts discontinued study treatment for AE. No Grade 5 AEs were reported. Overall response rate (ORR), complete (CR) and partial (PR) response rates, n (%) [95% CI], and median PFS in DLBCL (95% CI) are shown in the table. Median PFS in the FL cohorts are not reported due to insufficient follow-up duration. Table PoV (CD79b) + R PiV (CD22) + R PoV [1.8 mg/kg] + R (Cohort C) R/R DLBCL ORR CR PR mPFS (mo.) N=39 22 (56%) [41, 71] 6 (15%) [7, 30] 16 (41%) [26, 58] 5.4 (2.8-8.4) N=42 24 (57%) [41, 72] 10 (24%) [12, 39] 14 (33%) [20, 48] 5.2 (4.1-NR) N/A R/R FL ORR CR PR N=20 14 (70%) [47, 86] 8 (40%) [21, 64] 6 (30%) [14, 53] N=21 13 (62%) [40, 80] 2 (10%) [2, 30] 11 (52%) [30, 72] N=16 7 (44%) [20, 70] 0 7 (44%) [20, 70] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation. Pts receiving PoV at 1.8 mg/kg had proportionately lower exposure of antibody conjugated MMAE compared to pts treated at the 2.4 mg/kg dose level. Conclusions: PoV and PiV + R were generally well-tolerated with similar toxicity profiles. Neutropenia, PN, and diarrhea were the principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + R compared to PiV + R suggests greater clinical activity in r/r FL. Lower overall response rates were observed in r/r FL pts treated with a lower dose of PoV. Results based on longer follow-up to further assess differences in safety and tolerability between the two PoV doses in r/r FL will be presented. Additional data of pts who received crossover ADC + R treatment following documented disease progression on initial ADC + R treatment will also be presented. Combination studies of PoV + R with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Disclosures Morschhauser: Genentech/roche: Honoraria, travel grants Other; Celgene: advisory boards, advisory boards Other, Honoraria. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Flinn:Genentech, inc.: Research Funding. Advani:Genentech, inc.: Research Funding. Diefenbach:Genentech, inc.: Research Funding. Press:Genentech, inc.: Research Funding. Chen:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Salles:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly:Genentech, inc.: Research Funding. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Assouline:Roche: Honoraria, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hagenbeek:millenium: Membership on an entity's Board of Directors or advisory committees. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Yalamanchili:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Sharman:Gen: Research Funding.

scholarly journals Estimated Glomerular Filtration Rate Is an Independent Predictor of Outcome in High-Risk Myelodysplastic Syndrome (MDS) and Low Blast Count Acute Myeloid Leukaemia (AML) Patients Treated with Azacytidine (AZA). a Retrospective Study from the MDS Registry of the Hellenic MDS Study Group

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5423-5423
Author(s):  
Sotirios Papageorgiou ◽  
Vasileios Papadopoulos ◽  
Papoutselis Menelaos ◽  
Anthi Bouhla ◽  
Argiris Symeonidis ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Performance Status ◽  
Univariate Analysis ◽  
Advisory Committees ◽  
Landmark Analysis ◽  
Kaplan Meier ◽  
Blast Count

Introduction. Myelodysplastic Syndrome (MDS) is a disease of the elderly. Apart from IPSS, IPSS-R and WPSS, several indexes incorporating patient comorbidities (such as the MDS CI index- Della Porta et al Haematologica 2011, the HCT-CI index - Sorror et al Blood 2005) and performance status (the GFM index- Itzykson et al Blood 2011) have been used to predict outcome in MDS patients treated with azacytidine (AZA). We sought to investigate the effect of comorbidities on the outcome after AZA in a large group of patients from the MDS registry of the Hellenic MDS Study Group. Methods. The present study has been conducted as a retrospective observational cohort one. It included high-risk MDS and low blast count AML patients treated with AZA from 26 centers in Greece from 2007 to 2018. T-test and ANOVA were used to compare scale variables between two or more groups respectively. Univariate analysis of nominal and scale survival data was performed using Kaplan-Meier survival curves and Cox regression respectively. All variables achieving p<0.05 at univariate analysis were considered eligible for multivariate analysis; the latter was based on Cox regression method. Results. We analyzed 536 consecutive patients. Patient characteristics are depicted in Table 1. The median follow-up period was 27.5±4.8 months. 371 patients received at least four cycles of AZA and 165 patients received less than 4 cycles of AZA. Patients who received ≥4 cycles of AZA did not differ from those who received <4 cycles regarding gender, age, estimated Glomerular Filtration Rate (eGFR), cardiovascular, renal, and tumor comorbidities. Significantly higher IPSS-R and GFM scores at baseline were found in the group of patients receiving < 4 cycles of AZA compared to patients who received ≥ 4 cycles of AZA (p=0.042 and 0.05 respectively), while transfusion dependence at baseline occurred more often in patients who received ≥ 4 cycles of AZA (p=0.039). To assess the prognostic significance of risk factors on leukemia free survival (LFS) and overall survival (OS), univariate and multivariate analysis for the whole population was performed, as well as a landmark analysis for patients who were treated with at least 4 cycles of AZA. ECOG performance status and the presence of peripheral blasts were independent prognostic factors for LFS and OS for the whole cohort analysis while response to AZA and the presence of peripheral blasts were independent prognosticators for LFS and OS in the landmark analysis. In addition, prior low dose cytarabine was an independent adverse prognostic factor for LFS in the landmark analysis. As regards comorbidities, neither of MDS-CI, HCT-CI and GFM systems independently predicted LFS or OS in either analysis, but eGFR with a cut-off of 45 ml/min was a strong and independent prognosticator for LFS and OS in both the standard and the landmark analysis. Kaplan-Meier survival curves regarding LFS and OS at AZA initiation and landmark analysis after 4th cycle of AZA in relation with eGFR are shown in Figure 1. Conclusion. This is the first study to demonstrate the importance of eGFR at baseline as a prognostic marker for LFS and OS in high-risk MDS and low-blast AML patients treated with AZA. The role of comorbidities and PS needs to be further evaluated in this patient group. Disclosures Symeonidis: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vassilakopoulos:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Panayiotidis:Bayer: Other: Support of clinical trial. Pappa:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kotsianidis:Celgene: Research Funding.

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