scholarly journals Rituximab Plus Chlorambucil As First-Line Treatment for Chronic Lymphocytic Leukemia: Final Analysis of an Open-Label Phase II Study

2014 ◽  
Vol 32 (12) ◽  
pp. 1236-1241 ◽  
Author(s):  
Peter Hillmen ◽  
John G. Gribben ◽  
George A. Follows ◽  
Donald Milligan ◽  
Hazem A. Sayala ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Therapeutic Option ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Response Rates ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Open Label

Purpose Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. Patients and Methods Patients with first-line CLL were treated with rituximab (375 mg/m2 on day 1, cycle one, and 500 mg/m2 thereafter) plus chlorambucil (10 mg/m2/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. Results A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. Conclusion These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.

scholarly journals Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia

2019 ◽  
Vol 3 (7) ◽  
pp. 1167-1174 ◽  
Author(s):  
Benjamin L. Lampson ◽  
Haesook T. Kim ◽  
Matthew S. Davids ◽  
Jeremy S. Abramson ◽  
Arnold S. Freedman ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
First Line ◽  
Open Label ◽  
Phase 2 Trial ◽  
Treatment Naïve ◽  
Line Setting

Abstract PI3 kinase (PI3K) activity is critical for survival of neoplastic B cells in patients with chronic lymphocytic leukemia (CLL). Blockade of PI3K signaling with idelalisib is effective for the treatment of relapsed CLL in combination with the anti-CD20 antibody ofatumumab. In this single-arm, open-label, nonrandomized phase 2 study, we investigated the efficacy and safety of idelalisib with ofatumumab in 27 patients with treatment-naïve CLL in need of therapy. Patients were planned to receive idelalisib for 2 monthly cycles, then idelalisib and ofatumumab for 6 cycles, followed by idelalisib indefinitely. The study was closed early and all patients ceased therapy when an increased rate of death as a result of infection was observed on other first-line idelalisib trials. Median time on therapy was 8.1 months, and median duration of follow-up was 39.7 months. We previously reported high rates of hepatotoxicity in a smaller cohort of patients in this trial; toxicities necessitated therapy discontinuation in 15 patients after a median of 7.7 months. The most frequent grade ≥3 adverse events were transaminitis (52% of patients), neutropenia (33%), and colitis/diarrhea (15%). The best overall response rate (ORR) was 88.9%, including 1 complete response. Median progression-free survival (PFS) was 23 months (95% confidence interval [CI], 18-36 months); 11 patients have not yet required second-line therapy. Idelalisib and ofatumumab demonstrated an unacceptable safety profile in the first-line setting, which resulted in a short PFS despite a high ORR. Future development of PI3K inhibitors for use in treatment-naïve CLL will require novel approaches to mitigate toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02135133.

scholarly journals First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase 3 iLLUMINATE trial

Haematologica ◽  
2022 ◽  
Author(s):  
Carol Moreno ◽  
Richard Greil ◽  
Fatih Demirkan ◽  
Alessandra Tedeschi ◽  
Bertrand Anz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Final Analysis ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
First Line Therapy ◽  
Line Therapy ◽  
Open Label Phase

iLLUMINATE is a randomized, open-label phase 3 study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or

scholarly journals Consolidation Therapy With Subcutaneous Alemtuzumab After Fludarabine and Rituximab Induction Therapy for Previously Untreated Chronic Lymphocytic Leukemia: Final Analysis of CALGB 10101

2010 ◽  
Vol 28 (29) ◽  
pp. 4500-4506 ◽  
Author(s):  
Thomas S. Lin ◽  
Kathleen A. Donohue ◽  
John C. Byrd ◽  
Margaret S. Lucas ◽  
Eva E. Hoke ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Serious Infections ◽  
Listeria Meningitis ◽  
Intent To Treat

PurposeTo determine if alemtuzumab consolidation improves response rate and progression-free survival (PFS) after induction chemoimmunotherapy in previously untreated symptomatic patients with chronic lymphocytic leukemia.Patients and MethodsPatients (n = 102) received fludarabine 25 mg/m2intravenously days 1 to 5 and rituximab 50 mg/m2day 1, 325 mg/m2day 3, and 375 mg/m2day 5 of cycle 1 and then 375 mg/m2day 1 of cycles 2 to 6; fludarabine plus rituximab (FR) administration was repeated every 28 days for six cycles. Three months after completion of FR, patients with stable disease or better response received subcutaneous alemtuzumab 3 mg day 1, 10 mg day 3, and 30 mg day 5 and then 30 mg three times per week for 5 weeks.ResultsOverall response (OR), complete response (CR), and partial response (PR) rates were 90%, 29%, and 61% after FR, respectively; 15% of patients were minimal residual disease (MRD) negative. Of 102 patients, 58 received alemtuzumab; 28 (61%) of 46 patients achieving PR after FR attained CR after alemtuzumab. By intent to treat (n = 102), OR and CR rates were 90% and 57% after alemtuzumab, respectively; 42% of patients became MRD negative. With median follow-up of 36 months, median PFS was 36 months, 2-year PFS was 72%, and 2-year OS was 86%. In patients achieving CR after FR, alemtuzumab was associated with five deaths resulting from infection (viral and Listeria meningitis and Legionella, cytomegalovirus, and Pneumocystis pneumonias), which occurred up to 7 months after last therapy. The study was amended to exclude CR patients from receiving alemtuzumab.ConclusionAlemtuzumab consolidation improved CR and MRD-negative rates after FR induction but caused serious infections in patients who had already achieved CR after induction and did not improve 2-year PFS or survival.

Randomized comparison of weekly or every-3-week (q3w) nab-paclitaxel compared to q3w docetaxel as first-line therapy in patients (pts) with metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1032-1032 ◽  
Author(s):  
W. Gradishar ◽  
D. Krasnojon ◽  
S. Cheporov ◽  
A. Makhson ◽  
G. Manikhas ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Response Rates ◽  
Complete Response ◽  
First Line ◽  
Open Label ◽  
First Line Therapy ◽  
Primary Endpoints ◽  
Ecog Ps

1032 Background: 130-nM albumin-bound (nab™) paclitaxel combines paclitaxel with albumin without solvents or altering either component. A cross analysis of 2 clinical trials comparing solvent-based (SB) paclitaxel 175 mg/m2 q3w to nab- paclitaxel (Gradishar et al, JCO, 2005) and SB docetaxel (Jones et al, JCO, 2005) suggested comparable antitumor activity between nab-paclitaxel and SB docetaxel and better tolerability with nab-paclitaxel in pts with MBC. The aim of this study was to compare the toxicity and antitumor activity of 3 regimens of nab-paclitaxel (q3w and 2 weekly) with each other and that of SB docetaxel in MBC. Methods: In this open-label study, first-line pts with MBC were randomly assigned to nab-paclitaxel 300 mg/m2 q3w (A); nab-paclitaxel 100 mg/m2 (B) or 150 mg/m2 (C) days 1, 8, and 15, q28 days (q 3/4 w); or SB docetaxel 100 mg/m2 q3w (D). The primary endpoints were overall response rate (complete response + partial response, evaluated q8w) and toxicity. Progression-free survival (PFS) was also determined. Results: 302 pts (median age, 54 years; 99% Caucasian; 75% postmenopausal; ECOG PS =2 [94% =1]) either had at least 2 response assessments (94%) or had discontinued due to PD (6%). The efficacy results are shown in the Table . Neutropenia (N) was greater with D than with A, B, or C (p < 0.001). Grade 4 N was: A) 4%, B) 3%, C) 7%, and D) 74%. Febrile neutropenia (FN) was: A) 1%, B) 1%, C) 1%, and D) 7%. Gr 3 peripheral neuropathy was: A) 14%, B) 7%, C) 12%, and D) 5%. Conclusions: The response rates of q3w nab-paclitaxel and solvent-based docetaxel were comparable. Q 3/4 W nab-paclitaxel resulted in higher response rates than solvent-based docetaxel. Grade 4 N and FN were less frequent with nab-paclitaxel as compared with solvent-based docetaxel. To date, all 3 nab-paclitaxel regimens have a longer PFS than SB docetaxel although the data are not yet mature (33% of events). Final data for a radiological review of response data, PFS, and toxicity will be presented. [Table: see text] No significant financial relationships to disclose.

Comparison of Cladribine Plus Cyclophosphamide With Fludarabine Plus Cyclophosphamide As First-Line Therapy for Chronic Lymphocytic Leukemia: A Phase III Randomized Study by the Polish Adult Leukemia Group (PALG-CLL3 Study)

2010 ◽  
Vol 28 (11) ◽  
pp. 1863-1869 ◽  
Author(s):  
Tadeusz Robak ◽  
Krzysztof Jamroziak ◽  
Joanna Gora-Tybor ◽  
Beata Stella-Holowiecka ◽  
Lech Konopka ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Deletion ◽  
Randomized Study ◽  
Nucleoside Analogs ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Tp53 Gene ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
First Line

Purpose Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacy and safety of cladribine and fludarabine, each combined with cyclophosphamide, in previously untreated progressive CLL. Patients and Methods Patients received cladribine at 0.12 mg/kg combined with cyclophosphamide at 250 mg/m2 for 3 days intravenously (CC regimen) or fludarabine at 25 mg/m2 combined with cyclophosphamide at 250 mg/m2 for 3 days intravenously (FC regimen), every 28 days for up to six cycles. The primary end point was complete response (CR) rate. Secondary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. Results Of 423 randomly assigned patients (211 to CC and 212 to FC), 395 were evaluated in the final analysis. The CR and ORR reached 47% and 88% in the CC arm and 46% and 82% in the FC arm (P = .25 and P = .11, respectively). The median PFS was 2.34 years with CC and 2.27 years with FC (P = .51). OS and grade 3/4 treatment-related toxicity were also comparable. Moreover, we did not observe any significant differences in CC and FC efficacy across different patient prognostic subgroups that included patients with 17p13 (TP53 gene) deletion who had poor survival in both study arms. Conclusion Cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe first-line regimens for progressive CLL. Both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion.

Preliminary phase II study results of capecitabine (X) + irinotecan (I) + bevacizumab (A) as first-line therapy for patients (pts) with metastatic colorectal cancer (MCRC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14502-14502
Author(s):  
S. Beslija ◽  
M. Banjin ◽  
S. Jungic ◽  
N. Obralic ◽  
G. Kecman-Malcic ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Response Rate ◽  
Early Stage ◽  
Progression Free Survival ◽  
Disease Stage ◽  
First Line ◽  
Open Label ◽  
First Line Therapy ◽  
Study Results

14502 Background: The oral fluoropyrimidine X (Xeloda®) has improved efficacy, safety and convenience compared with 5-FU/LV in MCRC [Van Cutsem et al. Br J Cancer 2004] and early-stage colon cancer [Twelves et al. NEJM 2005]. A recent study showed that I + X q2w is active and well tolerated [Garcia-Alfonso et al. ESMO 2006]. The humanized monoclonal antibody A (Avastin®) targets VEGF and limits tumor angiogenesis. The addition of A to 5-FU/LV/I (IFL regimen) results in significant improvements in survival among pts with MCRC [Hurwitz et al. NEJM 2004]. Replacing 5-FU/LV with X in this combination is a logical step forward. Here we report data from an open-label phase II trial of XIA in MCRC. Methods: Pts with untreated, histologically confirmed MCRC received I 175 mg/m2 i.v. d1, X 1000 mg/m2 orally bid d2–8, and A 5 mg/m2 d1. Treatment was repeated q2w x12 cycles in the absence of disease progression or unacceptable toxicity. Pts without progressive disease after 12 cycles of XIA continued on the same dose of A + X 1500 mg/m2 bid d2–8, q2w. The primary endpoint was progression-free survival (PFS); secondary endpoints were response rate (RECIST), overall survival (OS), safety, and quality of life. Results: 24 out of a planned total of 32 pts have been enrolled. Baseline characteristics are: M/F 50%/50%; median age 53 years (range 30–70); disease stage at initial diagnosis IIIA/IIIB/IV 29%/21%/50%; no. of metastatic sites 1/>1 50%/50%; most common metastatic site liver; prior adjuvant therapy 33% (Mayo 5-FU/LV). Pts received a median of 12 cycles (range 1–18) of XIA. All 24 pts are evaluable for safety and 22 for efficacy. The overall response rate is 77% (4 CR, 13 PR); 2 pts (9%) have stable disease and 3 have progressed. One pt has died. Median PFS and median OS have not yet been reached. The only grade 3 adverse events are diarrhea (13%), fatigue (4%), mucositis (4%), enteritis (4%), ileus (4%); there is one report of grade 4 leucopenia. All other adverse events are mild-to-moderate. Conclusions: The XIA combination appears to be highly active and well tolerated as first-line treatment for MCRC, providing support for further evaluation of this combination. No significant financial relationships to disclose.

scholarly journals Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 489-495 ◽  
Author(s):  
John C. Byrd ◽  
Thomas J. Kipps ◽  
Ian W. Flinn ◽  
Januaro Castro ◽  
Thomas S. Lin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Toxicity Profile ◽  
Dose Escalation Study ◽  
Free Survival ◽  
Previously Treated Patients ◽  
Previously Treated

AbstractPreclinical data demonstrate enhanced antitumor effect when lumiliximab, an anti-CD23 monoclonal antibody, is combined with fludarabine or rituximab. Clinical data from a phase 1 trial with lumiliximab demonstrated an acceptable toxicity profile in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). We therefore pursued a phase 1/2 dose-escalation study of lumiliximab added to fludarabine, cyclophosphamide, and rituximab (FCR) in previously treated CLL patients. Thirty-one patients received either 375 mg/m2 (n = 3) or 500 mg/m2 (n = 28) of lumiliximab in combination with FCR for 6 cycles. The toxicity profile was similar to that previously reported for FCR in treatment of relapsed CLL. The overall response rate was 65%, with 52% of patients achieving a complete response (CR), which compares favorably with the CR rate previously reported for the FCR regimen alone in relapsed CLL. The estimated median progression-free survival for all responders was 28.7 months. The addition of lumiliximab to FCR therapy is feasible, achieves a high CR rate, and does not appear to enhance toxicity in previously treated patients with CLL. A randomized trial comparing lumiliximab plus FCR with FCR alone is underway to define the benefit of this combination in relapsed CLL. This trial was registered at clinicaltrials.gov as NCT00103558.

scholarly journals A Phase II trial of Ofatumumab and Complement Replacement in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

2019 ◽  
Author(s):  
Joseph M Tuscano ◽  
Christina Poh ◽  
Aaron S Rosenberg ◽  
Brian A. Jonas ◽  
Gustavo Barisone ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Fresh Frozen Plasma ◽  
Lymphocytic Leukemia ◽  
Complement Activity ◽  
Fresh Frozen ◽  
Low Levels

Abstract Background: While many humanized monoclonal antibodies utilize complement dependent cytotoxicity, the complement depleting effects of these antibodies and the effect of complement replacement are not well-described. This study sought to examine complement levels and the effect of complement repletion after treatment with ofatumumab in patients with chronic lymphocytic leukemia (CLL). Methods: Twelve patients with relapsed or refractory CLL were treated with ofatumumab in combination with fresh frozen plasma used as complement replacement. The primary endpoint was objective response rate. Correlative endpoints included complement levels C3 and C4 and complement activity. Results: Adverse events were minimal, and efficacy was encouraging with an overall response rate of 83% and 2 patients (17%) achieving a complete response. While only 2 (17%) of patients had low complement activity at baseline, 8 (67%) developed low levels of complement activity. At a median follow-up time of 37 months the median progression-free survival was 12.5 months. Conclusions: While a minority of patients had low complement activity at baseline, a majority developed low levels of complement with ofatumumab treatment. The magnitude of complement depletion did not correlate with response. Future trials are needed to further explore complement replacement as a less toxic strategy to improve efficacy of monoclonal antibody-based regimens in CLL.

scholarly journals Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Blood ◽  
2019 ◽  
Vol 133 (26) ◽  
pp. 2765-2775 ◽  
Author(s):  
Ian W. Flinn ◽  
John G. Gribben ◽  
Martin J. S. Dyer ◽  
William Wierda ◽  
Michael B. Maris ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Standard Dose ◽  
Tumor Lysis Syndrome ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

Abstract This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (&lt;10−4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

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