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)

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.

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Safety and Efficacy of Bendamustine Monotherapy in the First-Line Treatment of Patients with Chronic Lymphocytic Leukemia: Polish Lymphoma Research Group Real-Life Analysis

Chemotherapy ◽

10.1159/000503220 ◽

2019 ◽

Vol 64 (3) ◽

pp. 155-162

Author(s):

Dariusz Wołowiec ◽

Agnieszka Szymczyk ◽

Stanisław Potoczek ◽

Dorota Krochmalczyk ◽

Daria Zawirska ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Research Group ◽

Alkylating Agents ◽

Real Life ◽

Nucleoside Analogs ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Cytostatic Drug ◽

First Line ◽

Safety And Efficacy

Bendamustine is a cytostatic drug with a unique structure, combining the features of purine nucleoside analogs and alkylating agents. In patients with chronic lymphocytic leukemia (CLL) it is commonly used in combination with rituximab (BR protocol) both in the first-line as well as subsequent lines of therapy, and in clinical trials it is often combined with new targeted therapies. Therefore, the data on its real-life safety and efficacy are of clinical significance. As the Polish Lymphoma Research Group (PLRG), we retrospectively analyzed the efficacy and tolerability of bendamustine monotherapy in 96 patients with CLL. The median number of bendamustine cycles was 5, and 44 patients did not complete the planned 6 cycles (46%). Among the adverse events associated with the earlier termination of bendamustine treatment, infections were the most common (20.5%), followed by neutropenia (15.9%) and thrombocytopenia (15.9%). Dose reductions and/or delays occurred in 31% of treatment cycles (132 of 425) with neutropenia (17.9%) as the most frequent cause. Efficacy analysis showed an overall response rate of 88.2% with complete remission and partial remission achieved in 43.8 and 41.7% of patients, respectively. At the 24th month of follow-up, progression-free survival was 52% and overall survival was 69.7%. Bendamustine in monotherapy was found to be safe and efficacious, at least in terms of early response. Special attention should be paid to infectious complications, and especially that immune disorders are characteristic in the clinical course of CLL. Our observations suggest efforts must be made to ensure the proper timing and proper dose in the administration of the drug, and to avoid the premature termination of the treatment.

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.49.6547 ◽

2014 ◽

Vol 32 (12) ◽

pp. 1236-1241 ◽

Cited By ~ 70

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.

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First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2009-02-206185 ◽

2009 ◽

Vol 114 (16) ◽

pp. 3382-3391 ◽

Cited By ~ 227

Author(s):

Barbara F. Eichhorst ◽

Raymonde Busch ◽

Stephan Stilgenbauer ◽

Martina Stauch ◽

Manuela A. Bergmann ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Elderly Patients ◽

Survival Time ◽

Remission Rate ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

First Line ◽

First Line Therapy ◽

Line Therapy

Abstract Although chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m2 for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight [BW] with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.

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Phase III Randomized Study of Bendamustine Compared With Chlorambucil in Previously Untreated Patients With Chronic Lymphocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.8389 ◽

2009 ◽

Vol 27 (26) ◽

pp. 4378-4384 ◽

Cited By ~ 307

Author(s):

Wolfgang U. Knauf ◽

Toshko Lissichkov ◽

Ali Aldaoud ◽

Anna Liberati ◽

Javier Loscertales ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

National Cancer Institute ◽

Randomized Study ◽

Progression Free Survival ◽

Normal Weight ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Response To Treatment ◽

Open Label ◽

Grade 3

PurposeThis randomized, open-label, parallel-group, multicenter study was designed to compare the efficacy and safety of bendamustine and chlorambucil in previously untreated patients with advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL).Patients and MethodsPatients (≤ 75 years of age) were randomly assigned to receive bendamustine 100 mg/m2/d intravenously on days 1 to 2, or chlorambucil 0.8 mg/kg (Broca's normal weight) orally on days 1 and 15; treatment cycles were repeated every 4 weeks for a maximum of six cycles. The response to treatment was assessed according to National Cancer Institute Working Group criteria, and the final determination of response was made by a blinded independent review committee.ResultsA total of 319 patients were randomly assigned (162 bendamustine, 157 chlorambucil). Complete or partial responses were achieved in 110 (68%) of 162 bendamustine-treated and 48 (31%) of 157 chlorambucil-treated patients (P < .0001). More patients showed complete responses with bendamustine than with chlorambucil (31% v 2%). Median progression-free survival was 21.6 months with bendamustine and 8.3 months with chlorambucil (P < .0001). Bendamustine was also associated with an improvement in duration of remission, compared with chlorambucil (median, 21.8 v 8.0 months). Hematologic National Cancer Institute Common Toxicity Criteria grade 3 to 4 adverse events were more common with bendamustine than with chlorambucil (occurring in 40% v 19% of patients). Severe infections (grade 3 to 4) occurred in 8% of bendamustine-treated patients and 3% of chlorambucil-treated patients.ConclusionBendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity profile, when used as first-line therapy in patients with advanced CLL.

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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 ◽

10.3324/haematol.2021.279012 ◽

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

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JUPITER-02: Randomized, double-blind, phase III study of toripalimab or placebo plus gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.lba2 ◽

2021 ◽

Vol 39 (18_suppl) ◽

pp. LBA2-LBA2

Author(s):

Rui-hua Xu ◽

Hai-Qiang Mai ◽

Qiu-Yan Chen ◽

Dongping Chen ◽

Chaosu Hu ◽

...

Keyword(s):

Interim Analysis ◽

Locally Advanced ◽

Progression Free Survival ◽

Final Analysis ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Double Blind ◽

Grade 3 ◽

First Line Treatment

LBA2 Background: Gemcitabine-cisplatin (GP) chemotherapy is the standard 1st line treatment for locally advanced, recurrent or metastatic (r/m) NPC. Toripalimab, a humanized IgG4K monoclonal antibody specific for PD-1, provided durable responses in patients (pts) with r/m NPC as monotherapy in the ≥2nd line setting (POLARIS-02 study). The results of JUPITER-02, a randomized, placebo-controlled, double-blinded Phase III trial of toripalimab in combination with GP chemotherapy as first-line treatment for r/m NPC are summarized. Methods: Pts with advanced NPC with no prior chemotherapy in the r/m setting were randomized (1:1) to receive toripalimab 240 mg or placebo d1 in combination with gemcitabine 1000 mg/m2 d1, d8 and cisplatin 80 mg/m2 d1 every 3 weeks (Q3W) for up to 6 cycles, followed by monotherapy with toripalimab or placebo Q3W until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors were ECOG PS (0 vs. 1) and extent of disease (recurrent vs. primary metastatic) at enrollment. Progression-free survival (PFS) and response were assessed by independent review committee (IRC) per RECIST v1.1. The primary endpoint was PFS by IRC in the ITT population. Secondary end points included ORR, DOR and OS. There was one prespecified interim analysis of PFS at 130 PFS events with a planned final analysis at 200 PFS events. Results: 289 pts were randomized: 146 to the toripalimab arm and 143 to the placebo arm. By May 30, 2020 as the interim analysis cutoff date, the median treatment duration was 39 weeks in the toripalimab arm and 36 weeks in the placebo arm. A significant improvement in PFS was detected for the toripalimab arm compared to the placebo arm (HR = 0.52 [95% CI: 0.36-0.74] two-sided p = 0.0003), with median PFS of 11.7 vs. 8.0 months. The 1-year PFS rates were 49% and 28% respectively. An improvement in PFS was observed across relevant subgroups, including all PD-L1 subgroups. The ORR was 77.4% vs. 66.4% (P = 0.033) and the median DOR was 10.0 vs. 5.7 months (HR = 0.50 [95% CI: 0.33-0.78]). As of Jan 15, 2021, OS was not mature, with 25 deaths in the toripalimab arm and 35 in the placebo arm (HR = 0.68 [95% CI: 0.41-1.14], P = 0.14). The incidence of Grade ≥3 adverse events (AEs) (89.0% vs 89.5%); AEs leading to discontinuation of toripalimab/placebo (7.5% vs 4.9%); and fatal AEs (2.7% vs 2.8%) were similar between two arms; however, immune-related (irAEs) (39.7% vs. 18.9%) and Grade ≥3 irAEs (7.5% vs. 0.7%) were more frequent in the toripalimab arm. Conclusions: The addition of toripalimab to GP chemotherapy as 1st-line treatment for pts with advanced NPC provided superior PFS and ORR and longer DOR than GP alone with a manageable safety profile. These results support the use of toripalimab with GP chemotherapy as the new standard care for this population. Clinical trial information: NCT03581786.

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Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.0838 ◽

2011 ◽

Vol 29 (16) ◽

pp. 2223-2229 ◽

Cited By ~ 170

Author(s):

David Gonzalez ◽

Pilar Martinez ◽

Rachel Wade ◽

Sarah Hockley ◽

David Oscier ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Survival Data ◽

Prognostic Value ◽

Gene Mutations ◽

Progression Free Survival ◽

Tp53 Gene ◽

Lymphocytic Leukemia ◽

Tp53 Mutations ◽

Mutational Status ◽

Gene Tp53

Purpose TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial. Patients and Methods We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data. Results Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value. Conclusion TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

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A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon- α2a as first-line therapy in metastatic renal cell carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3-3 ◽

Cited By ~ 62

Author(s):

B. Escudier ◽

P. Koralewski ◽

A. Pluzanska ◽

A. Ravaud ◽

S. Bracarda ◽

...

Keyword(s):

Progression Free Survival ◽

Final Analysis ◽

Phase Iii ◽

First Line ◽

Double Blind ◽

Phase Iii Trial ◽

First Line Therapy ◽

Interferon Α2a ◽

Phase Iii Study ◽

Adequate Organ Function

3 Background: Bevacizumab (BEV) is a monoclonal antibody that inhibits tumor angiogenesis by targeting VEGF. In relapsed RCC, BEV improved time to progression compared with placebo (2.5 vs. 4.8 months). A phase III trial was conducted to evaluate the efficacy and safety of BEV in combination with interferon (IFN)-a2a as first-line treatment in metastatic (m) RCC. The final analysis of progression-free survival (PFS) and interim analysis of overall survival (OS) are presented. Methods: Nephrectomized patients with clear cell mRCC, KPS of =70%, no CNS metastases and adequate organ function received IFN- a2a (x3/week at a recommended dose of 9 MIU for up to 1 year) plus BEV (10mg/kg q2w) or placebo until disease progression. Tumor assessments were performed every 8 weeks until week 32 and 12 weekly thereafter. Patients were stratified according to country and Motzer score. Results: Between June 2004 and October 2006, 649 patients were randomized (641 treated) at 101 centers in 18 countries. The treatment arms were well balanced for prognostic factors. At the data cutoff, 505 progression events had occurred, 111 patients remained on treatment, 287 had discontinued (discontinuations due to AEs were 12% with IFN vs. 28% with IFN-a2a/BEV), and 251 died. BEV-related side effects were generally mild and consistent with previous observations. The addition of BEV to IFN-a2a significantly increased PFS (10.2 vs. 5.4 mo) (HR=0.63; p<0.0001) and objective tumor response rate (30.6% vs. 12.4%; p<0.0001). A trend toward improved OS was observed with the addition of BEV to IFN-a2a (p=0.0670). Conclusions: BEV improves PFS when combined with IFN-a2a in mRCC. No unexpected safety events were observed. [Table: see text] [Table: see text]

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Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.192 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 192-192 ◽

Cited By ~ 52

Author(s):

Ghassan K. Abou-Alfa ◽

Donna Niedzwieski ◽

Jennifer J. Knox ◽

Andreas Kaubisch ◽

James Posey ◽

...

Keyword(s):

Overall Survival ◽

Hepatic Failure ◽

Randomized Study ◽

Locally Advanced ◽

Progression Free Survival ◽

Final Analysis ◽

Phase Iii ◽

Secondary Malignancy ◽

Advanced Hepatocellular Carcinoma ◽

Prior Systemic Therapy

192 Background: An exploratory analysis of a randomized phase II study in HCC comparing doxorubicin (D) alone to doxorubicin plus sorafenib (D+S) showed a significant improvement in overall survival favoring D+S (JAMA, 2011). The results appeared promising compared to the historic outcomes seen in the pivotal sorafenib (S) trials. CALGB 80802 was designed to determine if D+S improved survival compared to S alone. Methods: Patients with histologically proven advanced HCC, no prior systemic therapy and Child-Pugh A were randomized to receive D 60 mg/m2 every 21 days plus S 400 mg PO twice daily (D+S) or S alone. For bilirubin ≥ 1.3x normal, D and S doses were halved. D was maxed out at 360 mg/m2. The study was stratified by extent of disease (locally advanced; metastatic), the primary endpoint was overall survival (OS); and secondary endpoint progression-free survival (PFS). The final analysis was to occur when 364 events were observed among 480 total patients, with 90% power to detect a 37% increase in median OS (10.7 to 14.7 months; 1-sided α = 0.05). Results: The Alliance DSMB halted the study after accrual of 346 patients (173 on each of D+S and S) when a futility boundary was crossed at a planned interim analysis. With 107 events in each arm, median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5 months (95% CI 7.4-14.3) for S with a hazard ratio (HR) 1.06 (95% CI 0.8-1.4) for D+S vs. S. Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1), respectively (HR = 0.90, 95% CI 0.72-1.2). There were 38 deaths on treatment: 18 on D+S and 20 on S. Among these 8 [sepsis (1), dysphagia (1), pneumonia (1), cardiac (2), hepatic failure (2), and not otherwise specified (1)] on D+S, and 3 [fatigue (1), hepatic failure (1), and a secondary malignancy (1)] on S, were at least possibly related to treatment. A maximum grade 3 or 4 only hematologic adverse events (AE) occurred in 37.8% of patients on D+S and 8.1% of patients on S. Non-hematologic AEs were comparable, in 63.6% and 61.5% of patients, respectively. Conclusions: The addition of D to S resulted in higher toxicity and did not improve OS or PFS. The S median OS of about 10 months is consistent with previous reports. NCI Grant U10CA180821 Clinical trial information: NCT01015833.

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