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

Blood ◽  
2009 ◽  
Vol 114 (16) ◽  
pp. 3382-3391 ◽  
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.

No Significant Clinical Benefit of First Line Therapy with Fludarabine (F) in Comparison to Chlorambucil (Clb) in Elderly Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Phase III Study of the German CLL Study Group (GCLLSG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 629-629 ◽  
Author(s):  
Barbara F. Eichhorst ◽  
Raymonde Busch ◽  
Martina Stauch ◽  
Manuela Bergmann ◽  
Matthias Ritgen ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Clinical Benefit ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Free Survival ◽  
Significant Clinical Benefit ◽  
First Line Therapy ◽  
Line Therapy ◽  
Phase Iii Study

Abstract Introduction: Treatment regimens based on purine analogues as F have become standard in first line therapy of younger or physically fit CLL pts. In these pts purine analogue-based regimens resulted in higher response rates and prolongation of progression free survival (PFS). Because it is not clear if elderly or physically non-fit pts benefit from more intense first line strategies as well, Clb is still widely used in first line therapy of elderly CLL pts. The GCLLSG initiated a phase III study (CLL5 protocol) to evaluate the effect of F versus (vs.) Clb in first line therapy of elderly patients with advanced CLL. Patients: 206 pts (F 101; Clb 105), older than 64 years, were enrolled between July 1999 and September 2004. 13 pts had to be excluded due to violation of exclusion/inclusion criteria. 15% of the pts were in Binet stage A, 47% in stage B, and 38% in stage C. The median pt age was 70 years (range 64 to 80). Pts were randomized to receive either F 25mg/mi.v. d1–5 q 28 days for 6 courses or Clb 0,4mg/kg ideal bodyweight (BW) (dose escalation up to 0.8mg/kg) q15d for up to 12 months. The mean number of administered courses was 4.9 in the F arm, the median duration of Clb treatment was 6.5 months (median dose 0.5 mg/kg). Results: After a median observation time of 41,5 months (mo) (range 1–89 mo) 165 pts (F 78; Clb 87) were evaluable for response and 184 (F 88; Clb 96) for progression free survival (PFS). In spite of a significantly higher complete remission rate (CRR) and overall response rate (ORR) in the F arm (CRR8% vs. 0%; p=0.008; ORR86% vs. 59%; p<0.001) no difference in the PFS was assessed (median PFS time 18.7 mo for F vs. 17.8 mo for Clb; p=0.72). Moreover, 46% of F treated pts in comparison to 34% Clb treated pts died so far, but overall survival (OS) curves showed no significant difference (median OS 45.9 mo vs. 63.6 mo, p=0.21). Analyzing PFS and OS separately for pts <70 years and ≥70 years no difference between both arms was assessed as well. Impaired creatinine clearance did not have any effect on PFS and OS as well as gender. Pts in the Clb arm received rescue treatment more frequently than F recipients (62% vs. 39%). Pts initially treated with Clb received for first relapse treatment Clb in 20%, F in 43%, F-based combinations in 17% and in 20% others. ORR to 2nd line F was 53% (10 of 19). Pts initially treated with F received in 26% each F-based combinations and CHOP regimen. Retreatment with F was administered in 12%, while 2 pts only received Clb. Conclusion: This long-term follow-up analysis shows that elderly pts have no significant clinical benefit from first line therapy with F in comparison to Clb. Though higher CRR and ORR F failed to show any benefit in terms of PFS and OS. A possible explanation for this phenomenon is the longer treatment period with Clb, that might prevent earlier relapses. Moreover, in case of relapse F treated pts received either no treatment at all or more intense regimen in comparison to Clb. In conclusion, Clb and F are similar potent first-line treatment options for elderly CLL pts.

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

Fludarabine Monophosphate as First Line Therapy for Chronic Lymphocytic Leukemia (CLL) - 11 Years Clinical Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4970-4970
Author(s):  
J.E. Novoa ◽  
A.L. Rojo ◽  
B. Beñaran ◽  
R. Draper ◽  
H. Calvo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Monoclonal Antibodies ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Response Rate ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Intravenous Formulation

Abstract Background: fludarabine (F) has become the standard first line therapy for chronic lymphocytic leukemia (CLL) in younger patients. Treatment of early stage patients with chlorambucil without risk stratification has not been shown to prolong survival. In recent years effective and potentially curative approaches such as nucleosides analogues, stem cell transplantation or monoclonal antibodies have been developed. The attraction of monoclonal antibodies is based on selective targeting of tumor - relevant surface markers and a distinct mechanism of action (antibody-dependent cellular cytotoxicity). Aims: to assess the efficacy, safety and quality of life of F in previously untreated B-cell CLL patients in a group of medical institutions in Uruguay during 11 years (1995–2006). Methods: 168 patients between the period 1995 – 2006 were evaluated.120 of them received F intravenous formulation (1995–2006) and 48 the oral one (2002–2006). Age: 48 – 85 years old, media 67 years old. Gender: male 90, female 78. Inclusion criteria for B-cell CLL was Binet stages B, C and A progressive (Ap), 18 to 85 years old, non multiorganic failure, performance status 0 – 2 (WHO), written informed consent. First condition was non previous treatment. Staging: Binet A 12/168, B 116/168 & C 40/168. Treatment: as first line therapy all the patients received (minimum): 6 cycles of i.v. Fludarabine (Fludara®, Schering) 25 mg/m2/daily (5 days) e/30 days or Oral Fludarabine, 40 mg/m2/daily (5 days), 6 cycles. Results: on this B-cell CLL cohort the overall response rate (ORR) was 78% (CR+PR), 80% of them have immunophenotypic response. Safety: on the 1100 cycles in 168 patients, the toxicity was: 1 AIHA, 2 pancytopenia, 3 plaquetopenia. Grade 3–4 infection rate was 1,3%. No alopecia was observed in any patient. Kaposi sarcoma (0,7%). Mortality rate: 1,7% (3/168 patients). Other adverse factors to overall survival were, age over 65 (p=0,0001) and hepatic impairment (p=0,0001). Toxicity: (WHO>2): granulocytopenia 28%, thrombocytopenia 8%, infection 2%. Although fludarabine-treated patients experienced more significant myelosuppression, no difference in the treatment group was demonstrated. Causes of death: Richter 12%, sepsis 5%, associated disease 34%, second malignancy 17% and others 30%. Comparing oral with intravenous formulation in overall survival the results were: CLL 34% vs 36% (p= NS). Conclusions: fludarabine monofosfate (Fludara®) looks like an effective and safe treatment for B-cell CLL. The oral and intravenous formulations have a similar response rate in elderly and young patients. The challenge remains to integrate new information to apply novel therapies in a disease-specific and risk-adapted maner. A longer follow up and a larger trial, might be needed to confirm these results.

Health related quality of life (HRQOL) evaluated with the EORTC C30 questionnaire in first line therapy of elderly patients with chronic lymphocytic leukemia (CLL): Results of a phase III trial of the German CLL Study Group (GCLLSG)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7572-7572 ◽  
Author(s):  
B. F. Eichhorst ◽  
R. Busch ◽  
M. Hallek
Keyword(s):  
Social Functioning ◽  
Age Groups ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Response To Treatment ◽  
First Line ◽  
Elderly Age ◽  
First Line Therapy ◽  
Line Therapy ◽  
Significant Difference

7572 Background: The GCLLSG evaluated the efficacy of fludarabine (F) versus (vs.) chlorambucil (Clb) in first line therapy of older patients with advanced CLL. HRQOL was evluated by using the EORTC C30 questionnaire. Methods: Pts were randomized to receive 6 courses of F (25 mg/m²/day (d) IV for 5d; 92 pts) or 12 months (mo) of Clb (0.4–0.8 mg/kg/d PO, every 15d; 99 pts). All pts were previously untreated, aged between 65 and 79 years and in advanced stage Binet C or symptomatic Binet B or A. Primary endpoints were overall survival (OS) and progression free survival (PFS), secondary endpoint was HRQOL. The EORTC C30 questionnaire (version 2.0) was sent to all patients at baseline and after 6, 12 and 24 mo. Scores (0–100) for 15 different measures (1 global HRQOL, 5 functional, 3 symptom and 6 single item scales) were evaluated at each time point. Results: F induced significantly higher response rates and prolonged the PFS, while no significant difference in OS was observed. At baseline 130 of 191 pts (68%) completed the questionnaires followed by more than 80% at mo 6 to 24. Compliance rates were similar in both treatment arms. Between pts completing questionnaires or not no statistically significant differences in perfomance status, age, stage or response to treatment were observed. HRQOL differences in comparison to baseline values were significantly improved after F treatment in global HRQOL, role and social functioning after 12 months as shown by the table. Responders had a significantly better global HRQOL and social functioning as well. Except for an impaired physical functioning no differences in HRQOL were observed between different age groups (65–69, 70–74, 75–79). Conclusion: Elderly F treated patients with CLL showed improvement inglobal HRQOL. Elderly age groups had a similar HRQOL as younger age groups. [Table: see text] [Table: see text]

Randomized Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid Plus Oxaliplatin As First-Line Therapy for Metastatic Colorectal Cancer

2008 ◽  
Vol 26 (12) ◽  
pp. 2006-2012 ◽  
Author(s):  
Jim Cassidy ◽  
Stephen Clarke ◽  
Eduardo Díaz-Rubio ◽  
Werner Scheithauer ◽  
Arie Figer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Folinic Acid ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Hand Foot Syndrome ◽  
Grade 3

PurposeTo evaluate whether capecitabine plus oxaliplatin (XELOX) is noninferior to fluorouracil. folinic acid, and oxaliplatin (FOLFOX-4) as first-line therapy in metastatic colorectal cancer (MCRC).Patients and MethodsThe initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX versus FOLFOX-4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 × 2 factorial design randomly assigned patients to XELOX versus FOLFOX-4, and then to also receive either bevacizumab or placebo. We report here the results of the analysis of the XELOX versus FOLFOX-4 arms. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecified primary end point for the noninferiority analysis was progression-free survival.ResultsThe intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1,400 patients after the start of the amended 2 × 2 design, for a total of 2,034 patients. The median PFS was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4–containing arms (hazard ratio [HR], 1.04; 97.5% CI, 0.93 to 1.16). The median overall survival was 19.8 months with XELOX versus 19.6 months with FOLFOX-4 (HR, 0.99; 97.5% CI, 0.88 to 1.12). FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX-4.ConclusionXELOX is noninferior to FOLFOX-4 as a first-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients.

Appropriate use of bendamustine in first-line therapy of chronic lymphocytic leukemia. Recommendations from SIE, SIES, GITMO Group

2014 ◽  
Vol 38 (11) ◽  
pp. 1269-1277 ◽  
Author(s):  
Antonio Cuneo ◽  
Monia Marchetti ◽  
Giovanni Barosi ◽  
Atto Billio ◽  
Maura Brugiatelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Appropriate Use ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy
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