Efficacy Outcomes of Treatments for Double Relapsed/Refractory Follicular Lymphoma (R/R FL): A Systematic Literature Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Brad S. Kahl ◽  
Anik R. Patel ◽  
Omer Zaidi ◽  
Sonya J. Snedecor ◽  
Anna G. Purdum
Keyword(s):  
Clinical Trials ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Clinical Data ◽  
Research Funding ◽  
Treatment Options ◽  
Unmet Need ◽  
Progression Free Survival ◽  
Disease Stage ◽  
Advisory Committees

ABSTRACT Introduction: Patients with indolent non-Hodgkin lymphomas (iNHL), including follicular lymphoma (FL), have high response to first-line treatment. However, retreatment is often required when relapses occur, and those with multiple relapses represent a patient population with an unmet need for effective treatment. Clinical data for several treatment options exist for the general relapsed and refractory (R/R) population; however, there are relatively fewer data specific to FL patients with ≥2 lines of prior treatment. This work systematically identified the available efficacy data in the double R/R FL population. Methods: The MEDLINE and EMBASE databases were searched through February 10, 2020. Studies were limited to interventional clinical trials of R/R FL patients (or mixed histologies with a predominance of FL) and articles published in English. Studies also must have reported one or more efficacy measures, such as overall response rate (ORR), complete response (CR), duration of response (DoR), time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Potential interventions of interest were lenalidomide ± rituximab (R), duvelisib, ibrutinib, venetoclax, polatuzumab vedotin + R, obinutuzumab, copanlisib, umbralisib, idelalisib, and tazemetostat. Results: Of 35 publications examining treatment outcomes in R/R FL patients, only 14 (representing 5 unique clinical trials) were specific to the ≥ 2-line population. These trials were: CHRONOS Part B (copanlisib), DAWN (ibrutinib), DELTA (idelalisib), DYNAMO (duvelisib), and Morschhauser et al. 2019 (tazemetostat) and included a total of 605 participants. All studies used similar inclusion criteria, and patients included were similar in age (median 62-65), disease stage (III/IV), and ECOG score (0-2). Patients in the CHRONOS study had a median number of prior treatments of 2, whereas those in the DELTA study had 5. ORR ranged from 21% (ibrutinib) to 59% (copanlisib) (Table). The DoR ranged from 8.3 months in tazemetostat patients with EZH2 gene mutation to 19.4 months for ibrutinib. PFS ranged from 5.7 months in tazemetostat patients with wild-type EZH2 to 11.2 months for copanlisib. Median TTNT was only reported in the DAWN study (16 months). Conclusions: Very few clinical data exist reporting efficacy outcomes specific to the double R/R FL population. The limited data indicate that current treatments do not produce durable responses for most double R/R FL patients, demonstrating an unmet need. Further research is needed to fully understand the efficacy and safety of other potential interventions for this population. Disclosures Kahl: Genentech:Consultancy;Pharmacyclics LLC:Consultancy;AstraZeneca Pharmaceuticals LP:Consultancy, Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene Corporation:Consultancy;AbbVie:Consultancy;Roche Laboratories Inc:Consultancy;BeiGene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta:Consultancy, Research Funding.Patel:Kite, a Gilead Company:Current Employment.Zaidi:BMS:Consultancy.Snedecor:Pharmerit - an OPEN Health Company:Other: Employment at consultancy paid by Kite Pharma to conduct this work.Purdum:Kite, a Gilead Company:Current Employment.

scholarly journals Benchmark of Progression Free Survival for Multiple Lines of Therapy in Follicular Lymphoma Treated in the Rituximab Era

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2955-2955 ◽  
Author(s):  
Anna Alperovich ◽  
Connie Batlevi ◽  
Katy Smith ◽  
Zhitao Ying ◽  
Jacob D Soumerai ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Complete Response ◽  
Line Treatment ◽  
Advisory Committees ◽  
Free Survival ◽  
Third Line ◽  
Third Line Treatment

Abstract Introduction In their lifetime, patients with follicular lymphoma frequently require multiple treatments, which have improved their survival over the past few decades. The expected treatment outcome based on lines of treatment in the post-Rituximab era is currently unknown. We analyzed the progression free survival and event free survival by line of treatment to aid estimating clinical endpoints when designing future clinical trials for multiply relapsed patients. Patients and Methods Adults (≥18 years) with de novo follicular lymphoma (FL) treated at our center between 1998 and 2007 were eligible (N=1134). 236 patients with ≤2 visits, mixed histology at initial diagnosis, and active concurrent malignancy were excluded. Of the remaining 898 patients, 105 were observed and did not require treatment during the timeframe of this dataset, and 2 had incomplete data, therefore 791 patients were eligible for response, progression and event free survival (PFS and EFS) analysis (Figure 1). Response was documented by investigators based on clinical or radiographic assessment. Complete response was based on radiographic assessment. PFS was defined as start of treatment to progression of disease or death. Patients with inadequate response to treatment, change of treatment, or stable disease without subsequent documented relapse were censored in the PFS analysis. Events for EFS were defined as progression, change of treatment, and death. PFS and EFS of sequential lines of treatment were evaluated by Kaplan-Meier method and compared across lines using log-rank test with adjustment for within-patient correlation. PFS and EFS were compared by other clinical variables using regular log-rank tests. Results Median age of diagnosis was 57.3 years with 1:1 male to female ratio. Median overall survival was not reached with median follow up of 9 years (N=898, range 0.2 - 16.8 years, Figure 1A). Median time to first treatment for the entire group was 2.3 months (range 0 - 13.3 years). In first line treatment of the 791 patients, 51% (N=406) received Rituximab with chemotherapy (R-Chemo), 13% (N=101) received chemotherapy only (Chemo), 19% (N=150) received Rituximab monotherapy (R-Mono), and 17% (N=129) received other treatments including radiation and surgery. For second line treatment, 405 patients were treated with about 37% receiving R-Chemo and 34% receiving R-Mono. As line of treatment increased, the percentage of patients with radiographically assessed complete response diminished from 71% at first line treatment to 25% by fifth line treatment (Figure 1B). Median PFS for first, second and third line treatment are 4.8, 1.6, and 1 year, respectively (Figure 2A). Median EFS for first, second and third line treatment are 3.8, 1.1, 0.8 year, respectively (Figure 2B). For subsequent lines of treatment, both median PFS and EFS were <1 year. Conclusion Follicular lymphoma is an indolent disease often requiring multiple lines of treatment. However, PFS and EFS for multiple lines of treatment in FL has not been described in the post-Rituximab era. The work has benchmarked the median response by line of treatment. After third line treatment, the PFS was ≤1 year. This analysis serves to aide comparison of different therapies for future drug approval in relapsed FL. Disclosures Hamlin: Xencor: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Horwitz:Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy; ADCT Therapeutics: Research Funding. Kumar:Celgene: Honoraria, Other: Scientific Advisory Board; Celgene: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding. Moskowitz:Merck: Honoraria; Seattle Genetics: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Moskowitz:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palomba:Pharmacyclics: Consultancy. Zelenetz:Gilead Sciences: Research Funding.

Treatment of Early Stage Nodal Follicular Lymphoma Using Involved-Field Radiotherapy and Rituximab: Preliminary Results of the Mir Trial (phase II study of the German Low Grade Lymphoma Study Group (GLSG))

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1634-1634 ◽  
Author(s):  
Klaus Herfarth ◽  
Marianne Engelhard ◽  
Peter Borchmann ◽  
Karin Hohloch ◽  
Volker Budach ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Early Stage ◽  
Progression Free Survival ◽  
Large Field ◽  
Advisory Committees ◽  
Free Survival ◽  
Involved Field ◽  
Involved Field Radiotherapy

Abstract Abstract 1634 Background: The commonly recommended treatment for early stage follicular lymphoma grade 1 or grade 2 (stage I/II) is involved-field radiotherapy (IF RT). However, a prospective German trial showed improved progression free survival compared to historical data using large field radiation techniques as extended-field radiotherapy or total lymphatic irradiation (Stuschke et al, Cancer, 80, 1997). This trial led to the conclusion that large volume radiation techniques may prevent relapses of microscopic lymphatic disease and is confirmed by the a new study, which was presented at Lugano 2011 (Engelhard et al., Ann Oncol, 22 Suppl4, 2011). However, those extensive radiation protocols are associated with significant toxicities, especially grade 3 and grade 4 adverse events concerning the hematopoietic system. It has been shown that the CD20 antibody Rituximab also has an anti lymphoma activity in CD20 positive follicular lymphoma. It might prevent out field recurrences in case of involved field radiotherapy. The German Low Grade Lymphoma Study Group (GLSG) and the German Radiation Oncology Group (ARO) of the German Cancer Society conducted a prospective, multicenter phase II trial investigating the efficacy and toxicity of a combined involved-field radiotherapy in combination with Rituximab treatment (MIR = MabThera and Involved field Radiotherapy) with an accrual of 85 patients (ClinicalTrials.gov Identifier: NCT00509184). Patients and Methods: 85 patients (47 male / 38 female) with early stage CD20 positive follicular lymphoma grade 1/2 were included in the trial at 16 German centers between February 2007 and October 2010. Median age at diagnosis was 55 years (21–75 years). Stage I disease was diagnosed in 48 patients and Stage II in 37 patients. Macroscopically left lymphoma after diagnostic surgery was observed in 55 patients, no macroscopic lymphoma in 26 patients and an equivocal status (e.g. due to postoperative tissue changes) in 4 patients. The treatment included a first block of Rituximab (4 weekly cycles; 375 mg/m2body surface), a 4 week treatment gap with a restaging CT / planning CT of the involved region in week 7 and followed by another block of Rituximab(4 weekly cycles) concurrently with an IF RT of 40 Gy for macroscopic tumor or 30 Gy in case of a complete remission (CR). The fractionation schedule was 5×2Gy per week. Primary endpoint of the study was progression free survival (PFS) at 2 years. Secondary endpoints were CR rate after Rituximab monotherapy (week 7) and after complete treatment (week 18). Additional endpoints were relapse rate, relapse pattern, overall survival, toxicity and quality of life. The protocol was approved by the ethics committee of the University of Heidelberg Medical School and the Paul-Ehrlich-Institute (PEI-registration number 432/06). The trial was in accordance to the Declaration of Helsinki. Recruitment was finished in October 2010. Clinical report form (CRF) collection is currently under way. Results: The treatment was well tolerated. There were 16 serious adverse events (SAE; toxicity grade 3 or higher): 3 infections, 1 hypersensitivity, 2 cardiac disorders, 1 vascular disorder, 1 respiratory disorder, 2 gastrointestinal disorders, 4 bone injuries. Two patients died due to secondary neoplasm. 3/16 were considered to be related to the treatment. Eight patients had to be excluded from the primary response evaluation due to failed inclusion criteria (e.g. stage, histology.) or early withdrawal of their consent. The mean follow-up of the remaining 78 patients has been 22.3 +/− 11.4 months, so far. Of 55 patients with remaining macroscopic lymphoma at inclusion, 26% showed a CR at week 7 after 4 cycles Rituximab (15% missing, CRF data still have to be collected). The CR rate improved to 60% at week 18 at the first follow-up examination at week 18 (15% of data still missing) and to 80% at month 6 (22% of data still missing). A total of 8 relapses have been detected (1 infield relapse) so far. The 2 years actuarial progression free survival and overall survival has been estimated to be 90% and 96%, respectively. Conclusion: The combination of Rituximab and IF RT in early stage nodal follicular lymphoma grade 1/2 is well tolerated and shows promising initial results. So far, 2 years PFS matches with that of large field radiotherapy without the accompanying toxicity and is superior to historic data of IF RT only. Disclosures: Herfarth: Roche: Honoraria, Research Funding. Borchmann:Roche: Honoraria, Research Funding. Budach:Roche: Honoraria. Viardot:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Witzens-Harig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Support of (other) clinical trials and Scientific Advisory Boards Other.

Sequential Immune Cell Modulation in Nordic Follicular Lymphoma Patients in the SAKK 35/10 Randomized Trial with Rituximab and Lenalidomide

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1535-1535 ◽  
Author(s):  
Sandra Lockmer ◽  
Björn E Wahlin ◽  
Bjorn Ostenstad ◽  
Åsa Jeppson-Ahlberg ◽  
Birgitta Sander ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Nk Cells ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Immune Cell ◽  
Nk Cell ◽  
Disease Stage ◽  
Advisory Committees ◽  
Immune Cell Subsets

Abstract Background Follicular lymphoma (FL) is the second most common lymphoma in adults. Although responsive to therapies it is still considered incurable. The introduction of the CD20 antibody rituximab is well known to have improved outcome. Rituximab acts through complement-mediated cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC) and direct induction of apoptosis. To enhance the efficacy of rituximab, different combination regimens have been used, mostly with chemotherapy but also with cytokines. Lenalidomide, an immunomodulatory agent commonly used in the treatment of multiple myeloma, has been shown to induce durable responses with manageable toxicity in indolent lymphomas and mantle cell lymphoma, especially in combination with rituximab. It acts on both the malignant cells and their microenvironment. The drug modulates signaling pathways, enhances the capacity of T cells and increases ADCC by natural killer (NK) cells, as well as suppresses angiogenesis. When combined with rituximab, the clinical effects seem to be synergistic (Fowler 2014). We aimed to investigate the dynamics of immune cell subsets in peripheral blood in patients given rituximab with or without lenalidomide. Patients and Methods FL patients included in a multicenter randomized phase II trial performed by the Swiss Group for Clinical Cancer Research (SAKK) in collaboration with the Nordic Lymphoma Group (NLG) were randomized 1:1 to treatment either with rituximab alone or rituximab and lenalidomide. Inclusion criteria were histologically confirmed CD20+ FL grade 1, 2 or 3A in disease stage Ann Arbor III-IV (or II not suitable for radiotherapy). Patients had to be in need of systemic therapy because of clinical symptoms, cytopenia, bulky disease or significant disease progression. In both treatment arms rituximab was administered as 4 single infusions of 375 mg/m2 weeks 1, 2, 3 and 4; in patients who showed at least a minor response 4 additional infusions were administered at weeks 12, 13, 14 and 15. In the combination arm, lenalidomide, 15 mg p.o. daily, was started 14 days before the first infusion and given continuously until 14 days after the last. Peripheral blood cells were sequentially sampled: at baseline, after 2 weeks' use of lenalidomide, 24 hours after first rituximab infusion and at follow-up at weeks 10 and 23. Analyses of CD3+, CD4+, CD8+ and CD56+CD3- (NK) cells were performed with flow cytometry. Results Immune cell activity was assessed on blood samples of 28 Norwegian and Swedish patients until July 2015. In all patients, irrespective of treatment arm, NK cell numbers markedly decreased at 24 hours after the first rituximab infusion compared to baseline counts (P=0.046), but returned to baseline levels by week 10 in most. However, patients in the combination arm exhibited a heterogeneous response with a diverse NK cell depletion/proliferation pattern, some showing a transient rise already after 14 days of lenalidomide use (Figure 1). CD3 levels were not affected at 24 hours after rituximab but increased over time in 15 of 18 patients (without differences between treatment arms). The increase at week 23 was statistically significant (P=0.004) with a median of 1.4 x 109 /L CD3+ cells compared to a baseline median of 0.88 x 109/L. In all patients, independent of treatment arm, the CD4/CD8 ratio increased compared to baseline already 24 hours after rituximab (P=0.011) and persisted throughout the study (week 10, P=0,005; week 23, P=0.019). The increased ratio was due to a large rise in CD4 counts (week 10, P=0.014; week 23, P=0.003), and a less pronounced rise in CD8 counts (week 10, P=0.094; week 23, P=0.007; Figure 2). Conclusion We found changes in the composition of immune cell subsets in peripheral blood in rituximab treated FL patients, with a larger interindividual variation when combined with lenalidomide. Ongoing analyses will reveal whether these patterns of immune cell response correlate with clinical outcome and long-term treatment effects. Figure 1. NK cell absolute counts (x 109/L) in (a) patients treated with rituximab and in (b) patients treated with rituximab plus lenalidomide. 1=baseline, 2=after 14 days of lenalidomide (b only), 3=24h after rituximab, 4=week 10, 5=week 23. Figure 1. NK cell absolute counts (x 109/L) in (a) patients treated with rituximab and in (b) patients treated with rituximab plus lenalidomide. 1=baseline, 2=after 14 days of lenalidomide (b only), 3=24h after rituximab, 4=week 10, 5=week 23. Figure 2. CD4/CD8 ratios in all 28 patients. The y scale is logarithmic. 1=baseline, 2=after 14 days of lenalidomide (14 patients only), 3=24h after rituximab, 4=week 10, 5=week 23. Figure 2. CD4/CD8 ratios in all 28 patients. The y scale is logarithmic. 1=baseline, 2=after 14 days of lenalidomide (14 patients only), 3=24h after rituximab, 4=week 10, 5=week 23. Figure 3. Figure 3. Disclosures Off Label Use: Lenalidomide was used together with rituximab in a randomized clinical trial.. Kimby:Gilead: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding.

scholarly journals Bayesian Network Modelling As a New Tool in Predicting of the Early Progression of Disease in Follicular Lymphoma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Vít K Procházka ◽  
Štěpánka Matuštíková ◽  
Tomáš Fürst ◽  
David Belada ◽  
Andrea Janíková ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Bayesian Network ◽  
Board Of Directors ◽  
Research Funding ◽  
Risk Groups ◽  
Response To Therapy ◽  
Disease Stage ◽  
Tumor Diameter ◽  
Advisory Committees ◽  
Individualized Prediction

Background: Twenty percent of patients (pts) with high-tumor burden follicular lymphoma (FL) develop progression/relapse of disease within 24 months of frontline immune-chemotherapy (POD24). Those ultra-high-risk cases are at 50% risk of dying within 5-years since the POD event. Unmet need is to identify such pts at the time of initial treatment. The traditional approach used for building predictive scores (such as FLIPI, PRIMA-PI) is multivariable logistic regression (LR). LR is the tool of choice in case of many predictors (continuous or categorical) and a single binary (yes/no) outcome. Bayesian network (BN) offer an alternative strategy which may overcome several drawbacks of LR (risk of overfitting, missing data handling, problems of odds ratio interpretation), brings more insight into the complex relations among the variables, and offer an individualized prediction. Aim: The goal was to build a model to predict the risk of POD24 from the parameters known at diagnosis and compare LR to BN approach. Methods: The study (ClinicalTrials.gov No NCT03199066) comprised 1394 FL (grade I-IIIA) patients from the Czech Lymphoma Study Group registry treated with frontline rituximab-containing regimen and diagnosed between 10. 4. 2000 and 28. 12. 2016. The following parameters were analyzed: gender, age at diagnosis, clinical stage, lymphoma grade, no. of LNs regions, bone marrow involvement, no. of extranodal localizations, longest tumor diameter, systemic symptoms, performance status, LDH, beta-2-microglobulin, hemoglobin, and leucocyte, lymphocyte, and thrombocyte counts, induction regime, radiotherapy, ASCT, maintenance application, response to treatment, and OS, PFS and POD24 as outcome parameters. POD24 was defined as relapse, progression, change of therapy for 24 months since the induction started. Only parameters known at diagnosis were used for the prediction of POD24. Results: The median age was 59 yrs (range 26-89 yrs) with female predominance (59.2%), advanced disease stage (III/IV) was seen in 85.9% of the cases and FLIPI risk groups distribution was as follows: low (18.8%), intermediate (30.9%) and high (50.3%). The most frequent regime used was R-CHOP (76.8%), followed by R-CVP (12.4%), R-bendamustine (4.7%), intensive protocols (3.3), and fludarabine-based (2.8%). Consolidative IF-radiotherapy was applied in 5.1% and up-front ASCT in 2.9% of the pts. Maintenance immunotherapy was given in 67.1% of the pts. Response to therapy was known in all but 28 pts (98%) with CR/CRu 67.9%, PR 26.6%, SD 1.8%, and PD in 3.2% of the cases. After a median follow-up of 7.64 yrs, 484 (34.7%) of the pts progressed or relapsed and 316 (22.6%) have died. POD24 was recorded in 266 (19.0%) of the pts. The 5-year OS reached 86.4% and 5-year PFS 64.2%. LR model (PFS) building strategy included testing for significance as this model performed better than the model with all parameters. Overfitting was prevented by splitting the data into training (75%) and testing (25%) set. The performance of the model was assessed using the AUC criterion computed on the ROC curve. The LR model reached AUC of 0.69, and at 80% specificity, it reached about 51% sensitivity. Next, the BN (Augmented Naïve Bayes Classifier) was trained. Links of all predictors to POD24 were forced and all links to age and gender were forbidden, otherwise the network structure was inferred from the data. The performance of the BN was similar to the LR - AUC of 0.67 and about 50% sensitivity at the specificity of 80%. Both these models were compared to the standard PRIMA-PI risk classifier and were found to better stratify the population into risk groups (Table 1). An example of a patient is presented who was low-risk according to PRIMA-PI but actually experienced the POD24 event. The BN estimated the probability of the event to 91% (Figure 1). Conclusion: Lymphoma-related death following POD24 remains the most frequent cause of mortality in FL patients. BN modelling is a non-inferior prognostic tool compared to LR in term of POD24 prediction. Unlike LR, it also allows visualisation of complex relations among the predictors and individualized prediction of the patient's POD24 risk, even if some of the predictors are unknown. Both "ad hoc" trained LR and BN were found to better stratify the population into risk groups with respect to POD24 event than the traditional PRIMA-PI score. Acknowledgement: MZ Czech Republic DRO grant (FNOL, 00098892). Disclosures Procházka: F. Hoffmann-La Roche AG: Consultancy, Honoraria; Takeda Pharmaceuticals, Inc: Consultancy, Research Funding. Belada:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Trněný:Janssen: Consultancy, Honoraria, Other: Travel Expenses; Gilead: Consultancy, Honoraria, Other: Travel Expenses; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy.

scholarly journals Impact of Immunochemotherapy with R-Bendamustine or R-CHOP in the Post-Induction Management of Treatment Naïve Advanced Stage Follicular Lymphoma Patients: A Subset Analysis of the FOLL12 Trial By the Fondazione Italiana Linfomi (FIL)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 811-811
Author(s):  
Stefano Luminari ◽  
Maria Elena Nizzoli ◽  
Annalisa Chiarenza ◽  
Donato Mannina ◽  
Alessandra Tucci ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
Tumor Burden ◽  
Molecular Response ◽  
Advisory Committees ◽  
Free Survival ◽  
Post Induction

Abstract Introduction. The administration of immuno-chemotherapy (ICT) followed by rituximab maintenance (RM) is the recommended approach for the front-line therapy of high tumor burden follicular lymphoma (HTB-FL) patients. Among available ICT regimens, RB (Rituximab-bendamustine) and R-CHOP regimen, are preferred options with high, similar efficacy. Regarding RM, its use is strongly supported after R-CHOP by the results of the PRIMA randomized trial; conversely, no prospective data are available to confirm the efficacy of RM in patients initially treated with RB. The FOLL12 trial was conducted to try to demonstrate that a response adapted post induction management of patients with HTB-FL could be as effective as standard RM in terms of Progression Free Survival (PFS). The trial actually showed the better efficacy of standard RM compared to the experimental approach thus providing indirect confirmation of the efficacy of RM after ICT, 10 years after the PRIMA trial. We here analyse the impact of initial ICT in the FOLL12 study that left treatment choice between RB and R-CHOP at physician discretion and on an individual patient basis. Methods. FOLL12 is a multicenter, randomized, phase III trial that compared standard RM vs. a response adapted post induction management in treatment naïve adult patients with grade 1-3a, stage II-IV and a HTB-FL. All patients received induction immunochemotherapy with 6 cycles of either R-CHOP or R-Bendamustine both followed by two additional doses of rituximab. Choice of ICT was at the physicians' discretion. After ICT, patients in the standard arm received bimonthly rituximab for up to two years. Patients in the experimental arm were managed according to centrally reviewed metabolic and molecular response. Patients achieving complete metabolic (CMR) and molecular response were managed with observation only, those in CMR with molecular persistence received 4 weekly rituximab doses. Patients not achieving CMR were treated with radioimmunotherapy with ibritumomab tiuxetan followed by standard RM. Primary study endpoint was 3 years progression free survival (PFS). Results. A total of 786 eligible patients were enrolled and 1:1 randomized either to standard or experimental arm. By backbone therapy, 341 patients received RB and 445 received RCHOP induction immunochemotherapy. RB was more frequently prescribed in older and female patients (OR 1.6, p=0.001) whereas RCHOP was preferred in patients with bulky disease (&gt;6cm) and grade 3a histology (OR 0.65, p=0.013). The median follow-up of the analysis was 56 months (range 1-71). In the non-randomized comparison between RB and RCHOP, no difference in terms of PFS was observed between the two regimens (HR for RB 1.07, 95%CI 0.83-1.38, p=0.597, Figure 1). Standard maintenance arm was more effective than experimental arm both in patients initially treated with RCHOP and in those treated with RB (HR RCHOP 1.61, 95% CI 1.16-2.25; HR RB 1.89, 95% CI 1.27-2.82). An unequal interaction between RB and RCHOP and post-induction therapy was observed for sex and for bone marrow involvement. Considering grade 3 to 5 adverse events (AEs), neutropenia was less frequently observed in RB (35.7%) compared to RCHOP (46.2%). Among extra-hematological AEs, higher frequency of grade 3-4 infections and of cutaneous toxicity were observed in RB treated patients (3.8% vs. 1.2% and 2.4% vs. 0.2%). Overall, 54 second malignancies (SM) have been observed including 23 hematologic malignancies and 31 solid cancers. Cumulative incidence of secondary cancer (excluding non melanoma skin cancers) at 3 and 5 years was 3.7% (95%CI 2.4-5.3%) and 8.1% (95%CI 5.8-10.9%). Conclusion. The current update of the FOLL12 trial demonstrated superiority of standard RM compared to the response adapted post induction management irrespective of prescribed regimen thus proving a first prospective non-randomized evidence of RM efficacy in patients with high tumor burden follicular lymphoma patients treated with RB. Both R-CHOP and RB were associated with a similar efficacy profile. Figure 1. Progression free survival for the standard maintenance arm (A) versus response oriented experimental arm (B) of the FOLL12 trial in patients treated with R-CHOP or R-Bendamustine (RB). Figure 1 Figure 1. Disclosures Luminari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Other: Travel, Accomodations, Expenses; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; GENELAB SRL: Consultancy; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ferrero: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau. Arcaini: Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene: Speakers Bureau; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses. Pulsoni: Roche: Consultancy, Speakers Bureau; Takeda, Pfizer, Sandoz, Merk: Consultancy; Gilead, Bristol: Speakers Bureau. Musuraca: Janssen, Roche, Incyte: Honoraria; Janssen, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen, Incyte, Roche: Consultancy.

scholarly journals Outcomes of Follicular Lymphoma Patients By Dynamic FLIPI at Diagnosis and Initial Treatment in the Post-Rituximab Era

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4119-4119
Author(s):  
Connie Batlevi ◽  
Anna Alperovich ◽  
Katy Smith ◽  
Zhitao Ying ◽  
Jacob D Soumerai ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Initial Treatment ◽  
Research Funding ◽  
Risk Group ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Genetics Research ◽  
Time To First Treatment

Abstract Background: Prognosis of follicular lymphoma (FL) has long been defined by the FLIPI score (Solal-Céligny et al., 2004) which is a 5 factor risk model consisting of age, stage, lactate dehydrogenase, hemoglobin and number of nodal areas. The FLIPI model has been validated at diagnosis in both the pre- and post-Rituximab eras. However, many patients are initially observed and have prolonged lead time from diagnosis to first treatment. In this study, we investigated whether FLIPI risk group at diagnosis changed by the time of initial treatment, and whether change of FLIPI risk group impacted treated outcome. Patients and Methods: All adult (≥18 yo) patients with de novo follicular lymphoma (FL) treated at our center between 1998 and 2007 were evaluated. Study excluded patients with ≤2 follow up visits, known divergent of composite histology at diagnosis, and active concurrent malignancies. FLIPI was scored at diagnosis and at initiation of first treatment. For patients with missing FLIPI data, FLIPI category was scored if the omission did not alter the FLIPI category. Stable FLIPI risk group was defined as FLIPI score being low or intermediate at diagnosis and at initiation of first treatment (Low-Low, Int-Int). Progressed FLIPI risk group was defined by the population which changed categories from low or intermediate at diagnosis to a higher category at initiation of treatment (Low-Int, Low-High, Int-High). FLIPI scores were available for 570 patients at both diagnosis and initial treatment. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier method and compared by log-rank tests. Time of diagnosis was used as time origin for OS analyses. When OS analyses involved FLIPI score at the first treatment, time of the first treatment was used as the entry time to adjust the risk sets to account for the fact that FLIPI at first treatment is unknown before the onset of the first treatment. Chi-squared tests and Fisher's exact tests were used to compare categorical variables by FLIPI score change status. Progression free survival before and after 24 months (PFS24) of initial therapy were calculated. Results: For 898 FL patients, median follow up was 9.2 years (range 0.23 - 16.84), median OS not reached. Based on FLIPI at diagnosis, the 5 year OS is 97.2% for low risk, 93.0% for int risk, and 80.2% for high risk, 10 yr OS is 90.9% for low risk, 77.7% for int risk, and 67.6% for high risk. Of 570 patients with FLIPI at diagnosis and first treatment, median time to first treatment was 0.18 years (range 0-12.5) for patients with stable FLIPI (N=280) and 2.70 years (range 0.01-13.33) for patients with progressed FLIPI (N=83). For patients observed ≥ 6 and 12 months, the median time to first treatment was 1.21 years (N=47, range 0.51-12.5) and 2.49 years (N=29, range 1.0-12.5) for patients with stable FLIPI and 3.77 years (N=62, range 0.54-13.3) and 3.92 years (N=57, range 1.13-13.3) for patients with progressed FLIPI, respectively. Progressed FLIPI was observed in 14.6% (83/570) of patients. The incidence of progressed FLIPI was 51.4% (57/111) in patients observed ≥1 year before initiating therapy. Parameters contributing to progressed FLIPI compared to stable FLIPI were decreased hemoglobin (29% versus 6%), increased nodal areas affected (43% versus 2%) and higher LDH (37% versus 5%). Patients with stable FLIPI had longer PFS at 12 and 24 months, 88.6% versus 73.8% (P=0.006) and 79.3% versus 66.1% (P= 0.031) (Figure 1). Analysis of patients initially observed ≥ 6 or 12 months demonstrated that progressed FLIPI negatively affected OS and PFS (Figure 2, observed ≥ 12 month data not shown). Median PFS for patients observed ≥ 6 months was 8.36 years for stable FLIPI, 3.14 years for progressed FLIPI. At observation of ≥ 12 months, median PFS was 6.25 and 3.22 years for stable and progressed FLIPI, respectively. Increased FLIPI was associated with increased risk of transformation throughout the disease course (25% vs 16%, P=0.039). Conclusion: Progressed FLIPI between diagnosis and first line treatment is associated with a reduced PFS, and increased incidence of histologic transformation. In patients who are initially observed, a progressed FLIPI reduces OS and PFS. The effect on PFS may be related to treatment bias and ongoing analysis is underway. Progressed FLIPI potentially identifies a population with heightened risk of transformation. Disclosures Hamlin: Seattle Genetics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Novartis: Research Funding; Molecular Templates: Research Funding; Xencor: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz:Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy; Huya: Consultancy; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Kumar:Celgene: Honoraria, Other: Scientific Advisory Board; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. Moskowitz:Bristol Myers Squibb: Honoraria; Merck: Honoraria; Seattle Genetics: Honoraria, Research Funding. Moskowitz:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palomba:Pharmacyclics: Consultancy. Zelenetz:Gilead Sciences: Research Funding.

Evolving Unmet Need in Patients Refractory to Lenalidomide: Overview of the Clinical Trials in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Maria-Victoria Mateos ◽  
Rohan Medhekar ◽  
Istvan Majer ◽  
Mehmet Turgut
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Literature Review ◽  
Board Of Directors ◽  
Unmet Need ◽  
Publicly Traded ◽  
First Line ◽  
Advisory Committees ◽  
Line Of Therapy

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.

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.

scholarly journals Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3543-3543 ◽  
Author(s):  
Alexis A. Thompson ◽  
Mark C. Walters ◽  
Janet L. Kwiatkowski ◽  
Suradej Hongeng ◽  
John B. Porter ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Adult Patients ◽  
Employment Equity ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were &lt;12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of &gt;11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of &gt;11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

Long-Term Efficacy and Safety (27 months) of the Biosimilar CT-P10 in Patients with Low Tumor Burden Follicular Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 27-28
Author(s):  
Larry W Kwak ◽  
Juan Manuel Sancho ◽  
Seok-Goo Cho ◽  
Hideyuki Nakazawa ◽  
Junji Suzumiya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Time To Progression ◽  
Advisory Committees ◽  
Free Survival ◽  
Travel Costs ◽  
Single Transition ◽  
Second Year

We assessed long-term safety and efficacy of CT-P10 and rituximab in patients with newly diagnosed low-tumour-burden follicular lymphoma (LTBFL), and following a single transition from rituximab to CT-P10. This double-blind, parallel-group, active-controlled phase 3 trial randomized patients with CD20+ LTBFL to receive CT-P10 or US-sourced rituximab (375 mg/m2 intravenous). Induction therapy (weekly for 4 cycles) was followed by a 2-year maintenance period for patients achieving disease control (CR, CRu, PR and SD). During the maintenance, CT-P10 or rituximab were administered every 8 weeks (6 cycles) in the first year and additional CT-P10 was administered every 8 weeks (6 cycles) in the second year. Secondary endpoints (reported here) were overall response rate during the study period, progression-free survival, time-to-progression, and overall survival. Safety and immunogenicity were also evaluated over the study period. Between Nov 9, 2015 and Jan 4, 2018, 258 patients were randomised (130 CT-P10; 128 rituximab). Over the study period, 115 (88%; CT-P10) and 111 (87%; rituximab) patients achieved overall response. At a median follow-up of 29·2 months (IQR: 26·1-33·7), median progression-free survival, time-to-progression, and overall survival were not estimable. The KM estimates (95% CI) for OS at 36 months were 98% (93-99) and 97% (89-99) in the CT-P10 and rituximab groups, respectively. Corresponding values for PFS were 80% (70-87) and 68% (54-79), while results for TTP were 82% (72-88) and 68% (54-79) in the CT-P10 and rituximab groups, respectively. (Figure A. OS; Figure B. PFS and Figure C. TTP) Over the study period, 114 (88%) and 104 (81%) patients in the CT-P10 and rituximab groups, respectively, experienced at least one treatment-emergent adverse event (TEAE) and 14 (11%) patients in each group experienced TE-serious adverse events (TESAEs). There were no unexpected safety findings observed during the second year of the maintenance period after single transition from rituximab to CT-P10. Figure 1 Disclosures Kwak: Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Xeme Biopharma/Theratest: Other: equity; CJ Healthcare: Consultancy; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Consultancy. Sancho:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gelgene: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Menne:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Speakers Bureau; Novartis: Honoraria, Other: Travel costs, Speakers Bureau; Pfizer: Honoraria, Other: Travel costs, Speakers Bureau; Celgene: Honoraria, Other: Travel grants; Roche: Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Astra Zeneca: Research Funding; Takeda: Honoraria, Speakers Bureau. Jurczak:Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Acerta: Research Funding; Bayer: Research Funding; Janssen: Research Funding; MeiPharma: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Trneny:Gilead: Consultancy, Honoraria, Other: Travel Expenses; Janssen: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Celgene: Consultancy; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses. Ogura:Cellgene: Honoraria; Chugai: Honoraria; Denovo Biopharma: Membership on an entity's Board of Directors or advisory committees; MejiSeika Pharma: Membership on an entity's Board of Directors or advisory committees; Mundi Pharma: Membership on an entity's Board of Directors or advisory committees; SymBio: Membership on an entity's Board of Directors or advisory committees; TevaTakeda: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Membership on an entity's Board of Directors or advisory committees. Kim:Pfizer: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; F. Hoffmann-La Roche: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding. Lee:Celltrion, Inc.: Current Employment. Kim:Celltrion, Inc.: Current Employment. Ahn:Celltrion, Inc.: Current Employment. Buske:Roche, Janssen, Bayer, MSD: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen, AbbVie, Pfizer, Celltrion: Honoraria, Speakers Bureau. OffLabel Disclosure: Rituximab monotherapy to LTBFL patients

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