Fixed-duration (FD) first-line treatment (tx) with ibrutinib (I) plus venetoclax (V) for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of the FD cohort of the phase 2 captivate study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7501-7501
Author(s):  
Paolo Ghia ◽  
John N. Allan ◽  
Tanya Siddiqi ◽  
Thomas J. Kipps ◽  
Ryan Jacobs ◽  
...  
Keyword(s):  
High Risk ◽  
Tp53 Mutation ◽  
Residual Disease ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Fixed Duration ◽  
Phase 2 ◽  
First Line ◽  
Primary Analysis ◽  
Color Flow

7501 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of first-line I+V in CLL. We previously reported results from the Minimal Residual Disease (MRD) cohort wherein undetectable MRD (uMRD) was achieved in over two-thirds of patients (pts) with 12 cycles of I+V, and 30-mo PFS rates were ≥95% irrespective of subsequent randomized treatment (Wierda, ASH 2020). We now present results from the FD cohort, evaluating fixed-duration tx with I+V. Methods: Pts aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Primary endpoint was CR rate, including CR with incomplete recovery (CRi); secondary endpoints were ORR, duration of response, uMRD rate (<10-4 by 8-color flow cytometry), PFS, OS, tumor lysis syndrome (TLS) risk reduction, and adverse events (AEs). Results: 159 pts were enrolled (median age 60 y). High-risk features included del(17p)/ TP53 mutation, 17%; del(11q), 18%; complex karyotype, 19%; and unmutated IGHV, 56%. 147 (92%) and 149 (94%) pts completed planned tx with I and V, respectively. Median time on study was 27.9 mo (range, 0.8–33.2). With fixed-duration I+V, CR rate was 55% (95% CI 48–63) in the overall population and was consistent across high-risk subgroups. Of the 88 pts who achieved CR, 78 (89%) had durable CR (duration ≥1 y); 1 died 7 mo after CR, and 9 with <1 y follow-up were not evaluable. ORR was 96%. Best uMRD response was achieved in 77% of pts in peripheral blood (PB) and 60% of pts in bone marrow (BM). 24-mo PFS was 95%; 24-mo OS was 98%. Results were similar in pts without del(17p) (n=136) (Table). In pts with del(17p)/ TP53 mutation (n=27), CR rate was 56%, uMRD rate was 81% (PB) and 41% (BM), and 24-mo PFS was 84% (95% CI 63–94). Of 34 pts with high baseline TLS risk based on tumor burden, 32 (94%) shifted to medium or low risk after I lead-in; no TLS occurred. AEs were primarily grade 1/2. Most common grade 3/4 AEs were neutropenia (33%), hypertension (6%), and neutrophil count decreased (5%). AEs led to discontinuation of I in 4% and V in 2%. Conclusions: First-line I+V is an all-oral, once-daily, chemotherapy-free, fixed-duration regimen that provides deep, durable responses in pts with CLL/SLL, including those with genomic high-risk features. CR, uMRD rates, PFS, and OS appear favorable. The safety profile of I+V was consistent with known AEs for each agent; no new safety signals were identified. Clinical trial information: NCT02910583. [Table: see text]

ZUMA-8: A phase 1/2 multicenter study evaluating KTE-X19 in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7566-TPS7566 ◽  
Author(s):  
Ian Flinn ◽  
Michael Marris ◽  
William G. Wierda ◽  
Steven Coutre ◽  
John M. Pagel ◽  
...  
Keyword(s):  
High Risk ◽  
Multicenter Study ◽  
Residual Disease ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
T Cell Therapy ◽  
Patient Reported

TPS7566 Background: Despite treatment advances, CLL is largely incurable. First-line targeted therapy with ibrutinib mostly produces durable remissions, but high-risk disease or many prior therapies increases relapse risk (Ghia P, et al. Haematologica. 2014). Relapse after ibrutinib is associated with a poor outcome (Maddocks KJ, et al. JAMA Oncol. 2015). Allogeneic stem cell transplantation potentially offers long-term remissions but has a high risk of morbidity/mortality (Shustik C, et al. Ann Hematol. 2017). Autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) with a CD28 costimulatory domain may be efficacious against CLL (Kochenderfer JN, et al. Blood. 2012). KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for R/R hematologic malignancies and may offer longer durable remissions with manageable safety in pts with R/R CLL. ZUMA-8 is a Phase 1/2 multicenter study for pts with R/R CLL. Methods: Adult pts must have R/R CLL with ≥ 2 prior treatment regimens, disease progression on ibrutinib, ECOG 0-1, and adequate organ function. Phase 1 will enroll 12-18 pts to assess dose-limiting toxicities (DLTs) with a 6 + 3 dose escalation/de-escalation design; 30 more pts may be enrolled to further assess safety. Phase 2 will enroll ≈60 pts to evaluate efficacy and safety. Pts will undergo leukapheresis followed by optional bridging therapy. Cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) conditioning chemotherapy will be given on Days -5, -4 and -3. KTE-X19 will be given on Day 0 at 0.5, 1 or 2 × 106 KTE-X19 cells/kg. The primary endpoint is incidence of DLTs for Phase 1 and independent review committee-assessed objective response rate (ORR) per iwCLL 2018 criteria for Phase 2. Secondary endpoints include complete remission (CR) rate, investigator-assessed ORR, minimal residual disease (MRD) negativity rate, MRD-negative CR rate, duration of response, progression-free survival, overall survival, safety, and patient-reported outcomes (Phase 2). Serum cytokine and blood KTE-X19 cell levels over time and level of anti-KTE-X19 antibodies are exploratory endpoints. Accrual is ongoing. Clinical trial information: NCT03624036.

Consolidation Therapy with Subcutaneous Alemtuzumab Following Induction Treatment with Oral FC (Fludarabine and Cyclophosphamide) in Previously Untreated Patients Aged 65-70 Years with Advanced Stage Chronic Lymphocytic Leukemia (CLL): A Phase II Trial of the FCGCLL/MW.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2831-2831 ◽  
Author(s):  
Alain Delmer ◽  
Stéphane Leprêtre ◽  
Bruno Cazin ◽  
Pierre Feugier ◽  
Olivier Tournilhac ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Phase Ii ◽  
Response Rate ◽  
Residual Disease ◽  
High Response Rate ◽  
Lymphocytic Leukemia ◽  
Stopping Rules ◽  
Induction Treatment ◽  
First Line ◽  
Color Flow

Abstract New treatment approaches in CLL aim at lowering as much as possible the level of minimal residual disease (MRD) to prolong the duration of response and eventually overall survival. Such a goal should be achieved by combining chemotherapy and monoclonal antibodies. The present phase II study was designed to evaluate the efficacy and the safety of first line therapy with 3 courses of oral fludarabine and cyclophosphamide (FC : F 40 mg/m² and C 250 mg/m² D1 to D3 every 4 weeks) followed by consolidation treatment with alemtuzumab in previously untreated patients (pts) aged 65 to 70 years with Binet stages B and C CLL. Pts achieving complete response (CR) and partial response (PR) after FC were eligible for the second part of the study i.e. consolidation with alemtuzumab administered subcutaneously (SC) at the dose of 10 mg thrice a week for 8 weeks. CMV antigenemia was monitored every week and alemtuzumab was discontinued in pts with more than 3 positive nuclei. MRD was evaluated before and during alemtuzumab treatment using a highly sensitive 6 color flow cytometry technique. Since severe infectious toxicity has been reported by others with similar strategies, FC regimen was limited to 3 courses and the duration of alemtuzumab treatment to 8 weeks with stringent stopping rules for CMV in this trial targeting a population of elderly pts in first line treatment. From June 2004 to June 2006, 42 pts have been enrolled in the study of whom 37 are assessable so far for induction treatment with FC. CR was achieved in 11 pts (30%) and PR in 17 pts (46%) for an overall response rate of 76% (28 pts). FC regimen was discontinued in 5 pts (13.5%) and stable disease was observed in 3 pts (8%). All the responding pts but one (one woman with onset of breast cancer) proceeded to alemtuzumab consolidation after a 2 month rest period. Alemtuzumab therapy has been completed in 16 pts, discontinued in 5 pts because of CMV reactivation as defined above (none of them developed CMV disease) and is still on going in 6 pts. Blood MRD assessment by flow cytometry was centralized in one center (RL) and could be performed in 19 pts with a set of 14 pts having been tested sequentially before alemtuzumab, after 4 weeks and after 8 weeks of treatment. In most cases, there was an impressive decrease of MRD level following alemtuzumab therapy and residual tumor cells were no longer detected. Detailed results of MRD study will be presented at the meeting. In conclusion, 3 courses of FC yielded a high response rate in previously untreated elderly CLL patients and SC alemtuzumab consolidation could thereafter be administered safely in most of them, resulting in a striking reduction of blood MRD.

Analysis of Minimal Residual Disease (MRD) from the Phase 2 Multicenter Study of Subcutaneous (SC) Alemtuzumab Combined with Fludarabine for Treatment of Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3111-3111 ◽  
Author(s):  
Christopher Flowers ◽  
Hilary Rosenthal ◽  
Jennifer Brown ◽  
Wendy Stock ◽  
Harvey Katzen ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Residual Disease ◽  
Pearson Correlation ◽  
Single Agent ◽  
Complete Response ◽  
Salvage Chemotherapy ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Color Flow ◽  
Prior Therapy

Abstract Introduction: In patients (pts) with relapsed/refractory CLL, responses achieved with conventional salvage chemotherapy may have limited durability, likely due to the presence of residual disease remaining in the bone marrow (BM) or peripheral blood (PB). The anti-CD52 monoclonal antibody alemtuzumab (Campath®) demonstrates single-agent efficacy in relapsed/refractory CLL and has been shown to induce MRD-negative (-) responses in 20% of pts (Moreton et al J Clin Oncol2005;23:2971–2979). A recent phase 2 study reported that treatment with SC alemtuzumab with or without the addition of oral fludarabine in pts with relapsed/refractory CLL resulted in a 49% overall response (OR) rate and 16% complete response (CR) rate; MRD(-) CR was achieved in 10% of pts (Sayala et al Blood2006;108: abstract 34). We evaluated the safety and efficacy of SC alemtuzumab combined with intravenous (IV) fludarabine in pts with previously treated CLL and report the responses and results from MRD analysis. Methods: Eligible pts had active CLL requiring therapy and had relapsed after at least 1 prior therapy. SC alemtuzumab 30 mg days 1–5 and IV fludarabine 25 mg/m2 days 1–5 were administered on a 28-day cycle for 4 cycles. Pts with <CR after 4 cycles were eligible to receive 2 additional cycles up to a total of 6 cycles. Responses were assessed based on the 1996 NCI Working Group Criteria. MRD was measured in the BM and PB at baseline, interim analysis, end of treatment, and 2 and 9 months following treatment. Four-color flow cytometry assays (CD5+/CD19+/CD38+/CD20[dim], CD5+/CD19+/CD43+/CD79b[dim], CD5+/CD19+/CD81+/CD22[dim]) were used to evaluate 200,000 to 1,000,000 events per sample, with lower limits of detection (LLD) ranging from 0.005% to 0.01% of leukocytes. Results: The study completed enrollment with 56 pts (median age 62 years, range 37–86; 54% Rai stage III/IV; median 3 prior lines of therapy, range 1–14) receiving at least 1 dose of study treatment; 28 pts (50%) completed 4 or more cycles of therapy and were evaluable for response; of these, 17 (30%) pts completed 5 or more cycles and 11 (20%) completed 6 cycles of therapy. MRD evaluation of the BM was available in 17 pts. The ORR among 28 evaluable pts was 64%, with CR in 6 pts (21%). Four of 6 pts in CR achieved MRD(-) in both BM and PB, which was maintained at last evaluation in all 4 pts. In addition, 9 pts with PR showed no evidence of disease in PB and/or BM below LLD, with 4 of these pts having undetectable disease in BM. The correlation between MRD(-) in the PB and BM was 0.63 and between MRD(-) by 4-color flow and CD5+/CD19+ <1% in the BM was 0.67 (Pearson correlation). Conclusion: After treatment with SC alemtuzumab and IV fludarabine, 64% of pts responded, with 8 of 17 evaluable pts achieving molecular undetectable disease in the BM, suggesting that MRD(-) remissions can be attained in a portion of heavily pretreated pts with CLL. Four-color flow cytometry of the BM is necessary to monitor MRD after an alemtuzumab regimen.

Prediction of Poor Outcome in CLL Patients Treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) in the CLL8 Trial of the German CLL Study Group (GCLLSG)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 977-977 ◽  
Author(s):  
Anna Fink ◽  
Raymonde Busch ◽  
Natali Pflug ◽  
Sebastian Boettcher ◽  
Dirk Winkler ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Poor Prognosis ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Rank Test ◽  
Advisory Committees ◽  
Color Flow ◽  
Poor Outcome ◽  
Increased Risk

Abstract Abstract 977 Introduction: For physically fit patients (pts) with chronic lymphocytic leukemia (CLL) the first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) is the new standard therapy. However, subgroup analyses in the CLL8 trial revealed that patients with a median progression free survival (PFS) of < 24 months after randomization showed a significantly shorter overall survival (OS) compared with pts achieving a PFS of ≥ 24 months. 15% of these patients were characterized by both, the presence of 17p deletions and TP53 gene mutations, another 7.5% by TP53 mutation alone. Interestingly, the majority of patients with a poor prognosis could not be defined by a mutation of p53 or del(17p). Therefore, an effort was made to further characterize the subgroup of patients with poor prognosis. Methods: In 143 patients out of 408 patients who received FCR in the CLL8 trial of the GCLLSG, an assessment of minimal residual disease (MRD) was available at final restaging. These patients were used for this analysis. Results for the primary endpoint PFS, the secondary endpoint OS, and central diagnostics performed for genomic aberrations by FISH and the IGHV gene status as well as for serum parameters before the start of therapy were available for all pts. MRD was determined at final restaging by multi-color flow cytometry from peripheral blood with a sensitivity of at least 10−4. The Kaplan-Meier method and the log-rank test were used to compare PFS and OS in pts with various combinations of risk factors. Results: This patient cohort used for the analysis was representative of the entire FCR population (n=408). There were no significant differences compared with the entire FCR population for age, ECOG status, B-symptoms, Binet or Rai stages, deletion of chromosome 17p, 11q, or 13q, trisomy 12, serum levels for s-TK or s-β2m. A combination of MRD levels of >10−2 or of MRD levels of >10−4 to <10−2plus at least one of the following three parameters (del(17p) or TP53 mutation or an unmutated IGHV-status) defined a group of patients at high risk of early progression (HR). The median PFS of HR pts was 22 months, the median PFS for patients defined as low risk (LR; n=103) was 69 months. HR patients had a 6.4 fold increased risk for progression (HR 6.4 95% CI: 3.970–10.347; p<0.0001) and a 5.7 fold increased risk for death, with a median OS of only 57 months (assessed from the beginning of FCR therapy). In contrast, median OS was not reached in the LR group at the time point of the analyses (HR 5.758, 95%CI:2.799–11.844, p<0.0001). Conclusion: The combined use of genetic markers and an MRD assessment at final restaging allows to identify CLL patients with a very poor outcome after FCR therapy. The high risk group identified by this approach should be treated within clinical trials using novel strategies including maintenance protocols or allogeneic stem cell transplantation. Disclosures: Fink: Hoffmann La Roche: Travel Grants. Pflug:Hoffmann La Roche: Travel Grants. Boettcher:Hoffmann La Roche: Honoraria, Travel Grants. Winkler:Hoffmann La Roche: Travel Grants. Ritgen:Hoffmann La Roche: Travel Grants. Fischer:Hoffmann La Roche: Travel Grants. Eichhorst:Hoffmann La Roche: Honoraria, Travel Grants. Wendtner:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Mendila:Hoffmann La Roche: Employment. Wenger:Hoffmann La Roche: Employment. Doehner:Hoffmann La Roche: Honoraria. Kneba:Hoffmann La Roche: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Hallek:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study

2021 ◽  
Author(s):  
William G. Wierda ◽  
John N. Allan ◽  
Tanya Siddiqi ◽  
Thomas J. Kipps ◽  
Stephen Opat ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Phase Ii ◽  
Residual Disease ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Tumor Lysis ◽  
Randomized Phase Ii ◽  
Minimal Residual

PURPOSE CAPTIVATE ( NCT02910583 ), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL). METHODS Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety. RESULTS One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, –1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time. CONCLUSION The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.

scholarly journals Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2062-2068 ◽  
Author(s):  
Sameer A. Parikh ◽  
Michael J. Keating ◽  
Susan O'Brien ◽  
Xuemei Wang ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Color Flow ◽  
Free Survival ◽  
Phase 2 Trial ◽  
End Of Treatment ◽  
Grade 3

Abstract Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation.

4-Jahres-Update der Murano-Studie bestätigt den Stellenwert von Venetoclax in der 2. Therapielinie der CLL

2021 ◽  
pp. 77-79
Author(s):  
Maximilian Schmutz ◽  
Sebastian Sommer
Keyword(s):  
Response Rate ◽  
Residual Disease ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Fixed Duration ◽  
Genetic Characteristics ◽  
Genomic Complexity ◽  
End Of Treatment

<b>Purpose:</b> In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics. <b>Patients and methods:</b> Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed. <b>Results:</b> Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC (<i>P</i> = 0.042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with <i>BIRC3</i> and <i>BRAF</i> mutations at EOCT and with <i>TP53, NOTCH1, XPO1,</i> and <i>BRAF</i> mutations at EOT. <b>Conclusion:</b> Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS. <b>Trial registration:</b> ClinicalTrials.gov NCT02005471.

Atezolizumab + obinutuzumab + venetoclax in patients with relapsed or refractory indolent non-Hodgkin’s lymphoma (R/R iNHL): Primary analysis of a phase 2 trial from LYSA.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7544-7544
Author(s):  
Charles Herbaux ◽  
Herve Ghesquieres ◽  
Reda Bouabdallah ◽  
Stephanie Guidez ◽  
Emmanuel Gyan ◽  
...  
Keyword(s):  
Tumor Lysis Syndrome ◽  
Safety Data ◽  
Induction Treatment ◽  
Phase 2 ◽  
Primary Analysis ◽  
Phase 2 Trial ◽  
Ann Arbor ◽  
Baseline Characteristics ◽  
Grade 3

7544 Background: R/R iNHL treatment remains challenging. Atezolizumab (ATE) and obinutuzumab (OBI) are monoclonal antibodies acting respectively to inhibit T-lymphocyte exhaustion or by inducing lymphoma cells cytotoxicity, whereas venetoclax (VEN) is a small molecule inhibiting BCL-2. Combining tumor-targeted therapies with agents that enhance anti-tumor immunity represents an attractive treatment paradigm. This LYSA sponsored multicenter phase 2 trial (NCT03276468) evaluated ATE, OBI and VEN combination in R/R B-cell lymphomas. Herein, we present primary efficacy and safety data from the iNHL cohort including Follicular Lymphoma (FL) and Marginal Zone Lymphomas (MZL). Methods: Patients ≥18 years with biopsy-confirmed R/R FL and MZL who failed at least one line of therapy were eligible. OBI was given IV at 1 g on day (D) 1, 8 and 15 of cycle (C) 1 and on D1 from C2 to C8 every 3 weeks. ATE was given IV, 1.2 g every 3 weeks, started at D2 of C1, then administered at D2 of each cycle for 24 cycles. VEN was given orally at 800 mg/D at full dose, starting on D8C1 for 24 cycles. The primary endpoint was the Overall Response Rate (ORR) evaluated by Lugano criteria at the end of induction (EOI) after 8 cycles of ATE, OBI and VEN (M6) or at premature treatment discontinuation. Results: At the time of the primary analysis (08 Jan 2021), 78 patients were enrolled. FL cohort (n = 58): the median follow-up was 14.5 months. Main baseline characteristics were: Ann Arbor Stage III/IV, 85.7%; FLIPI HR, 47.3%; > 2 prior lines of therapy, 32.1%; and exposed to ASCT, 30.4%. The ORR on PET scan at EOI was measured at 53.6% [41.8%-65.1%], including 30.4% of CMR. 37 patients (63%) received the full induction treatment. MZL cohort (n = 20; 13 nMZL, 5 eMZL, 2 sMZL): the median follow-up was 11.9 months. Main baseline characteristics were: Ann Arbor Stage IV, 100%; bone marrow infiltration, 38.9%; ≥ 2 extra-nodal sites, 50%; and > 2 prior lines of therapy, 22.2%. The ORR on CT scan at EOI was measured at 66.76% [44.6%-84.4%], including 16.7% of CR and 50.0% PR. 11 patients (55%) received the full induction treatment. At time of the present analysis, responses in the 2 cohorts seem durable with only 21,4% of responders who have reported relapse/progression. Out of the 78 pts, a total of 55 (70.5%) pts experienced grade 3–4 adverse event (AE) and 1 patient experienced an AE that led to discontinuation of any drug. Main AE of grade 3 or more were hematologic cytopenias, with only one febrile neutropenia (1.3%). Three pts experienced immune-related AE (1 grade 2 myositis and 2 grade 3 colitis), no tumor lysis syndrome was observed. Conclusions: ATE, OBI and VEN triplet appears to be well tolerated, with no unexpected toxicity brought by the combination. The ORR at EOI seems to be comparable to other innovative regiments in this setting, with durable responses to date. Clinical trial information: NCT03276468.

scholarly journals Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 405-411 ◽  
Author(s):  
Neil E. Kay ◽  
Susan M. Geyer ◽  
Timothy G. Call ◽  
Tait D. Shanafelt ◽  
Clive S. Zent ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Color Flow ◽  
Significant Clinical Activity ◽  
Minimal Residual

Abstract Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (> 70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.

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