5.27 Low-Dose Fludarabine and Cyclophosphamide Combined With Rituximab Is a Safe and Effective Treatment Option for Elderly and Comorbid Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Preliminary Results of Project Q-lite, by the Czech CLL Study Group

2011 ◽  
Vol 11 ◽  
pp. S261 ◽  
Author(s):  
Lukáš Smolej ◽  
Yvona Brychtová ◽  
Martin Špaček ◽  
Michael Doubek ◽  
David Belada ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Effective Treatment ◽  
Treatment Option ◽  
Low Dose ◽  
Lymphocytic Leukemia ◽  
Study Group ◽  
Small Lymphocytic Lymphoma ◽  
Effective Treatment Option ◽  
Preliminary Results

Low-Dose Fludarabine and Cyclophosphamide Combined with Rituximab In the Treatment of Elderly/Comorbid Patients with chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Preliminary Results of Project Q-Lite by Czech CLL Study Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2466-2466 ◽  
Author(s):  
Lukas Smolej ◽  
Martin Spacek ◽  
Yvona Brychtova ◽  
David Belada ◽  
Jiri Schwarz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Low Dose ◽  
Antimicrobial Prophylaxis ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Study Group ◽  
Bulky Disease ◽  
Intention To Treat ◽  
Serious Infections ◽  
Attending Physician

Abstract Abstract 2466 Background: Combination of fludarabine, cyclophosphamide and rituximab (FCR) is currently considered the treatment of choice in physically fit patients (pts) with chronic lymphocytic leukemia (CLL). However, many patients cannot tolerate this aggresive treatment because of advanced age and/or serious comorbid conditions. For these patients, chlorambucil has remained so far the standard of treatment. Low-dose fludarabine-based regimens have recently demonstrated promising results in small studies. Aims: to assess efficacy and safety of low-dose FC or FCR regimen used in elderly/comorbid patients with CLL. Patients and Methods: Between March 2009 and June 2010, we treated 74 pts with active disease (CLL, n=70, SLL, n=4, 57% males, median age, 70 years [range, 58–83], median Cumulative Illness Rating Score 4 [range, 0–10]) by low-dose FC/FCR at fourteen centers cooperating within Czech CLL Study Group. Dose reduction of chemotherapy was as follows: fludarabine to 50% (12 mg/m2 i.v. or 20 mg/m2 orally on Days 1–3), cyclophosphamide to 60% (150mg/m2 i.v./p.o. D1-3). The dose of rituximab was standard (375mg/m2 in 1st cycle, 500mg/m2 from 2nd cycle). The choice of regimen (FC vs FCR) was at the discretion of the attending physician. Treatment was repeated every 4 weeks. Antimicrobial prophylaxis with cotrimoxazole and aciclovir or equivalents was recommended. Fifty per cent of pts were treated in first line, the remaining half had relapsed/refractory CLL. Rai stage III/IV was present in 57% pts; 39% had bulky disease. IgVH genes were unmutated in 74%; according to hierarchical model, del 11q was present in 32% and del 17p in 8%. Results: FCR was used in 72 pts, FC in 2. Based on intention-to-treat principle, the overall response/complete response rate (including clinical CR and CR with incomplete blood count recovery) was 70/35%; 34 pts are still on treatment. No data on PFS/OS are available yet. Serious (CTC grade III/IV) neutropenia occurred in 51%, thrombocytopenia in 13% and anemia in 10% of pts. Serious infections were diagnosed in 13% of pts. Three pts (4%) died, all of them after failure of treatment (pneumonia, n=2, pulmonary embolism, n=1). Conclusions: Treatment of elderly/comorbid CLL patients with low-dose FC/FCR demonstrated very promising results. Toxicity was acceptable and manageable. Longer follow-up is needed for the assessment of PFS and OS. Supported by research project MZO 00179906 from Ministry of Health, Czech Republic. Disclosures: Smolej: Roche: Honoraria; Bayer-Schering: Honoraria; Genzyme: Honoraria. Off Label Use: Low-dose FCR in elderly/comorbid patients with CLL. Belada: Roche: Consultancy, Honoraria. Motyckova: Roche: Honoraria.

Low-Dose FCR Is a Safe and Effective Treatment Option for Elderly/Comorbid Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Updated Results of Project Q-Lite By Czech CLL Study Group

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4670-4670 ◽  
Author(s):  
Lukas Smolej ◽  
Yvona Brychtova ◽  
Michael Doubek ◽  
Eduard Cmunt ◽  
Martin Spacek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Study Group ◽  
Free Survival ◽  
Grade Iii

Abstract Background: Combination of fludarabine, cyclophosphamide and rituximab (FCR) is the current gold standard for physically fit patients (pts) with chronic lymphocytic leukemia (CLL). Nevertheless, many CLL patients cannot tolerate this intensive regimen owing to advanced age and/or serious comorbidities. Combination protocols based on dose-reduced fludarabine demonstrated promising results in pilot studies. Therefore, the Czech CLL Study Group initiated Project Q-lite, an observational study to assess efficacy and safety of low-dose FCR regimen used in elderly/comorbid patients with CLL/SLL. Updated results including progression-free survival (PFS), overall survival (OS) and multivariate analysis are presented. Patients and Methods: Between March 2009 and July 2012, a total of 207 pts with active disease (CLL, n=196, SLL, n=11) were treated by low-dose FCR at 16 centers cooperating within Czech CLL Study Group. Dose reductions of chemotherapy compared to full-dose FCR were: 50% of fludarabine (12 mg/m2 i.v. or 20 mg/m2 orally on days 1-3) and 60% of cyclophosphamide (150 mg/m2 i.v./p.o. on days 1-3). Rituximab was administered in standard schedule (375mg/m2 i.v. day 1 in 1st cycle, 500mg/m2 i.v. day 1 from 2nd cycle). Treatment was repeated every 4 weeks; antimicrobial prophylaxis with sulfamethoxazol/trimethoprim and aciclovir or equivalents was recommended. The basic characteristics are summarized in Table 1. Results: Based on intention-to-treat principle, the overall response rate / complete responses including clinical CR (without bone marrow biopsy) and CRi were 81/37% in 1st line and 63/30% in relapsed/refractory (R/R) disease. Serious (CTCAE grade III/IV) neutropenia was frequent (56 and 50%) but grade III/IV infections were only 15 and 18%. The most common causes of death were CLL progression and infections. At the median follow-up of 25 months, median progression-free survival (PFS) for previously untreated and R/R patients was 28 and 15 months; median overall survival (OS) has not been reached in previously untreated pts (75 % at 30 months) and was 30 months in R/R pts. Multivariate analysis identified del 11q, del 17p, bulky lymphadenopathy (1st line) and del 17p (R/R) as independent predictors of shorter PFS; absence of therapeutic response was the only factor associated with shorter OS (both in 1st line and R/R pts). Conclusions: Low-dose FCR appears to be an effective treatment for elderly/comorbid patients with CLL/SLL in first-line as well as R/R setting. Toxicity was acceptable and manageable. In historical comparison, efficacy of low-dose FCR compares favourably with chlorambucil monotherapy and is similar to obinutuzumab-chlorambucil combination from German CLL11 study. Interestingly, neither CIRS score nor creatinine clearance were predictive of PFS/OS. The study is registered at www.clinicaltrials.gov (NCT02156726). Fig 1. Fig 1. Disclosures Smolej: Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Travel grants, Travel grants Other; GlaxoSmithKline: Consultancy, Honoraria, Travel grants, Travel grants Other; Roche: Consultancy, Honoraria, Research Funding, Travel grants Other. Brychtova:Roche: Travel grants Other. Doubek:Roche: Consultancy; GlaxoSmithKline: Research Funding; Janssen: Consultancy. Spacek:Roche: Consultancy, Travel grants Other. Belada:Celgene: Research Funding; Roche: Consultancy, Research Funding, Travel grants, Travel grants Other; GlaxoSmithKline: Research Funding. Motyckova:Roche: Travel grants Other. Prochazka:Roche: Honoraria, Travel grants Other; Takeda: Speakers Bureau. Kozak:Roche: Honoraria, Travel grants Other.

Rituximab In Combination with High-Dose Dexamethasone: An Effective Treatment Option for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4629-4629
Author(s):  
Michael Doubek ◽  
Martin Simkovic ◽  
Anna Panovska ◽  
Monika Hrudkova ◽  
David Belada ◽  
...  
Keyword(s):  
Effective Treatment ◽  
Treatment Option ◽  
Progression Free Survival ◽  
Median Number ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Significant Activity ◽  
Effective Treatment Option ◽  
High Dose Dexamethasone

Abstract Abstract 4629 Background: Patients with refractory CLL have poor outcome despite currently used salvage treatment. Regimens based on high-dose corticosteroids seem to offer a promising treatment option in this scenario. High-dose methylprenisolone combined with rituximab (R-HDMP) demonstrated significant activity in relapsed/refractory CLL but serious infectious complications occurred in a substantial proportion of patients. Pilot data have shown that combination of dexamethasone and rituximab (R-Dex) may provide comparable results with less toxicity. Aims and Methods: We performed a retrospective analysis of the efficacy and safety of R-Dex in patients (pts) with CLL treated at two tertiary centers between April 2006 and February 2010. Patients received two versions of R-Dex regimen: the dose of rituximab was either 500 mg/m2 on day 1, 8, 15, 22 (375 mg/m2 in 1st cycle), repeated every 4 weeks (n=25) or 500 mg/m2 on day 1 (375 mg/m2 in 1st cycle) repeated every 3 weeks (n=16). The dose of dexamethasone was identical in both regimens: 320 mg per cycle (40 mg on day 1–4 and 10–13 or 15–18). Results: R-Dex was administered to 41 patients (19 males) with median age of 68 years (range, 44–81) indicated for treatment according to NCI-WG criteria. Autoimmune hemolytic anemia or thrombocytopenia was the only indication for the treatment in 7 patients. Rai stage III/IV was present in 37/41 pts. IgVH genes were unmutated in 24/29 pts with available results. Cytogenetic aberrations detected by FISH (n=33) revealed del 17p in 7 patients; del 11q in 11 patients; del 13q in 15 patients and trisomy 12 in 5 patients. Median number of previous therapies was 2 (0-8); 29/41 pts were previously treated with fludarabine-based regimens. The effect of R-Dex in evaluable patients without hemolysis (n=32) was: overall response rate (ORR), n= 21 (62%), complete remission (CR), n=6 (18%), partial remission (PR), n=15 (44%), stable disease (SD), n=4 (12%) and progressive disease (PD), n=5 (15%). All patients treated with R-Dex for autoimmune cytopenia achieved complete resolution of hemolysis. Grade III or IV toxicity included infections in 13 patients (32%), steroid diabetes in 6 patients (15%) and rituximab infusion-related side effects in 3 patients (7%). At the time of analysis (February 2010), median progression free survival (PFS) was 9 months; median overall survival has not been reached. There was no difference in ORR, PFS or OS between the two versions of R-Dex regimen. Conclusions: This pilot study shows that R-Dex is a feasible and effective treatment for relapsed/refractory CLL. In particular, R-Dex appears to be highly effective in CLL with autoimmune cytopenias. However, infectious toxicity remains a serious issue. In addition, long-term disease control can be expected in minority of patients only. Interestingly, higher dose of rituximab per cycle did not result in improved efficacy. Supported by research project MZO 00179906 from Ministry of Health, Czech Republic, by research grant MSM 0021620808 and by the Czech Leukemia Study Group for Life. Disclosures: Smolej: Roche: Honoraria; Bayer-Schering: Honoraria; Genzyme: Honoraria.

scholarly journals Risk of Serious Adverse Events, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Idelalisib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5489-5489
Author(s):  
Jonathan Kopel ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
Lukman Tijani ◽  
Ei Moe Phyu ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Conflicts Of Interest ◽  
Group Versus ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Study Group ◽  
Small Lymphocytic Lymphoma ◽  
Phase 3 ◽  
Serious Adverse Events

Introduction: Idelalisib is a first-in-class potent, oral, selective small-molecule inhibitor of δ isoform of phosphatidylinositol 3-kinase (PI3Kδ), which involves in the signaling of B-cell receptor pathways via activation of downstream serine threonine kinases AKT and mammalian target of rapamycin (mTOR), and has been implicated in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL). Yet, there are considerable safety concerns. We undertook a systematic review and combined analysis of phase 3 randomized controlled trials to determine the risk of serious adverse events, infection and sepsis in patients with relapsed/ refractory CLL/SLL treated with idelalisib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing idelalisib in patients with relapsed and refractory CLL/SLL that mention serious adverse events, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Three phase 3 RCTs with a total of 892 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 83, suggesting moderate heterogeneity among RCTs. The incidence of serious adverse events was 341 (69.59%) in study group vs 177 (44.03%) in control group with RR of 1.50 (95% CI: 1.28-1.75; p < 0.0001). Pneumonitis was noted in 14 (2.86%) vs 1 (0.25%) in control group (RR, 5.42; 95% CI: 1.22-24.13; p = 0.03). The incidence of any-grade pneumonia was 78 (15.92%) in study group vs 45 (11.19%) in control group (RR, 1.38; 95% CI: 0.98 - 1.96; P = 0.07). High-grade pneumonia was reported in 59 (12.04%) in idelalisib arm versus 33 (8.21%) in control group with RR of 1.36 (95% CI: 0.82 - 2.27; P = 0.23). Pneumocystis jiroveci (PJP) pneumonia rate was 2.56% higher in study group compared to control arm (RR, 4.25; 95% CI: 1.10 - 16.34; P = 0.04). Febrile neutropenia was noted in 13.47% in study group versus 4.73% in control arm (RR, 2.39; 95% CI: 0.90-6.34; p = 0.08). Sepsis rate was 3.36% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.64 (95% CI 1.10-6.30; p = 0.03). Treatment-related deaths were 45 (6.92%) in idelalisib arm vs 21 (3.74%) in control arm according to analysis of 2 trials. The pooled RR was not statistically significant at 1.64 (95% CI: 0.99 -2.71; P = 0.06). Conclusion: Patients on idelalisib experienced higher risk of serious adverse events, pneumonitis, PJP pneumonia, and sepsis, with RR of 1.50 for serious adverse events, RR of 5.42 for pneumonitis, RR of 4.25 for PJP pneumonia and RR of 2.64 for sepsis respectively. Nevertheless, there was no significant increase in treatment-related deaths due to TRAE in the idelalisib group, compared to control arm. Preemptive measures with proper supportive care are required to reduce those toxicities which can ultimately improve patients' quality of life and may probably affect patients' compliance. Disclosures No relevant conflicts of interest to declare.

Rituximab for Patients with Chronic Lymphocytic Leukemia: A Systematic Review

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4632-4632
Author(s):  
Kathrin Bauer ◽  
Olaf Weingart ◽  
Ina Monsef ◽  
Skoetz Nicole ◽  
Thomas Elter ◽  
...  
Keyword(s):  
Systematic Review ◽  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
Treatment Option ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Relative Effect ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Effective Treatment Option

Abstract Abstract 4632 Introduction: Chronic lymphocytic leukemia (CLL) accounts for 25% of all leukemias and remains incurable with conventional chemotherapy (CX). Rituximab (R) may be an effective treatment option for CLL patients with the potential to improve overall survival (OS) when given in combination with CX but there is also a risk of more side effects such as infections. This review aims to summarize the evidence for this new treatment option by evaluating the effects on OS, progression-free survival (PFS) and side effects. Methods: MEDLINE and CENTRAL were systematically searched for randomized controlled trials up to April 2010. Trials of patients with CLL comparing CX including R and treatment with CX alone (CX identical in both groups) were included. Clinical trials with previously untreated and pre-treated patients were explored in the main meta-analyses. Trial selection, quality assessment and data extraction were done independently by two review authors. Dichotomous data were analyzed as relative effect measures (i.e. relative risk, RR) with 95% confidence intervals (CI). Time-to-event outcomes were analyzed with hazard ratios (HR) and 95% CI in a random effects model. Results: A total of 992 records were screened. Two eligible trials with 921 untreated (GCLLSG CLL 8 trial (CLL8) and CALGB 9712 trial (CALGB 9712)) and two eligible trials with 604 pre-treated patients (REACH trial (REACH) and NCRI CLL 201 trial) that were fitting the inclusion criteria were identified. The NCLRI CLL 201 trial provided response data only. CALGB 9721 did not report HRs or P-values on OS or PFS and the survival curves for PFS and OS were of low quality, so the provided data were not included in the meta-analysis. Both, CLL8 and REACH examined patients receiving fludarabine (F) and cyclophosphamide (C) with or without R and were meta-analyzed with regard to PFS and OS. PFS (1342 patients) was significantly longer for FCR (HR 0.65, 95% CI [0.48, 0.88]). Analysis of OS (1368 patients) also showed a significantly longer survival for FCR (HR 0.73 (95% CI [0.58, 0.93]). CLL8 provided HRs for the different disease stages and showed significantly improved OS after FCR for Binet B patients only [Binet A: HR 0,19, 95% CI [0.23, 1.613]; Binet B: HR 0.45, 95% CI [0.295, 0.689]; Binet C: HR 1.4, 95% CI [0.843, 2.620]). REACH had not been significant regarding OS (HR 0.83, 95% CI [0.59, 1.17]). With regard to severe hematologic toxicity, meta-analysis of CLL8, REACH and CALGB 9721 showed a significantly higher risk of neutropenia (RR 1.46, CI 95% [1.03, 2.08]) for regimens including R, but there was no statistical difference for thrombocytopenia (RR 1.06, CI 95% [0.60, 1.87]), anemia (RR 0.89 [0.63, 1.26]) or the incidence of severe infections (RR 1.08 CI 95% [0.86, 1.35]). REACH reported a higher rate of secondary malignancies in the FCR-arm (FCR (7%), FC (5%)). Conclusions: This systematic review demonstrates significantly longer OS for CLL patients that received FCR compared to FC (HR 0.65, 95% CI [0.48, 0.88]) and confirms better PFS for patients receiving FCR (HR 0.73 (95% CI [0.58, 0.93]). Adverse events (particularly neutropenia) occurred more often when patients were treated with CX plus R but did not result in an increased infection rate. However, data of CLL8 were only available from the abstract and need to be subsequently confirmed. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document