Efficacy and safety of front-line therapy with fludarabine-cyclophosphamide-rituximab regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli CLL Study Group experience

Herishanu, Yair; Goldschmidt, Neta; Bairey, Osnat; Ruchlemer, Rosa; Fineman, Riva; Rahimi‐Levene, Naomi; Shvidel, Lev; Tadmor, Tamar; Aviv, Ariel; Braester, Andrea; Shapiro, Mika; Joffe, Erel; Polliack, Aaron

doi:10.3324/haematol.2014.115808

Cited by 19 publications

(14 citation statements)

References 30 publications

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“…Although the CR rate in our study was similar to that obtained in the CLL8 study, median PFS was unexpectedly shorter than in the CLL8 trial with standard‐dose FCR (56.8 months) . These variations in efficacy could probably be attributed to basic differences in the two patient populations and the total dose of chemotherapy given during the study period . In contrast to our study, the CLL8 trial included only physically fit patients with low comorbidity scores and good renal function (CCT ≥ 70 mL/min).…”

Section: Discussionsupporting

confidence: 55%

“…4,18 These variations in efficacy could probably be attributed to basic differences in the two patient populations and the total dose of chemotherapy given during the study period. 19 In contrast to our study, the CLL8 trial included only physically fit patients with low comorbidity scores and good renal function (CCT ≥ 70 mL/min). The good CR rated with low durability may also be attributed to the depth of response which may have been compromised by the reduced dose of FC given but could have been more accurately determined by evaluation of minimal residual disease assessment.…”

Section: Discussionmentioning

confidence: 90%

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Low‐dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD‐FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience

Herishanu

Tadmor

Braester

et al. 2019

Hematological Oncology

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Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. The fludarabine, cyclophosphamide, and rituximab (FCR) regimen is considered the treatment of choice for young fit patients with CLL; however, this combination is toxic for older patients. At the time this study was first planned and initiated, there was no standard chemo‐immunotherapy regimen regarded as standard therapy for the less fit elderly patient with CLL. Here, we conducted a single‐arm, phase II trial to examine the efficacy and safety of lower‐dose fludarabine and cyclophosphamide combined with a standard dose of rituximab (LD‐FCR) in elderly patients with previously untreated CLL. Forty patients received LD‐FCR and were included in the efficacy analysis. Two patients treated with FC alone were only included in the safety analysis. The median age was 72.7 years (range, 65.0 to 85.0). The overall response and complete response rates were 67.5% and 42.5%, respectively. Median progression‐free survival (PFS) was 35.5 months (95% CI, 29.27‐41.67). Two patients (4.8%) died during the study period. Hematological toxicities and infections were the most common complications encountered; grade 3 to 4 treatment‐related neutropenia occurred in 20 (47.6%) patients. During the entire study follow‐up, 26 patients (61.9%) had all grades of infection including six (14.3%) with neutropenic fever and eight (19%) with grade 3 to 4 non‐neutropenic infections. In conclusion, LD‐FCR is an effective and relatively safe regimen for previously untreated patients with CLL. It has the advantage of being both “time and cost limited” and, even in the era of novel agents, can still be considered when planning treatment for elderly patients without high‐risk biomarkers. However, recent results in fit elderly patients using the combination of bendamustine and rituximab which have achieved longer PFS with good safety profile must be taken into consideration in this regard.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 90%

Low‐dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD‐FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience

Herishanu

Tadmor

Braester

et al. 2019

Hematological Oncology

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“…The overall results of FCR therapy in the Israeli CLL group have been described previously, with a 70% clinical CR rate which corresponds to rates reported in the literature. 13 The current analysis includes 99 patients who had achieved a PR without lymphocytosis (<4.0 × 10 3 cells/μL) or a better response after FCR. Median age was 58 years with a male predominance 73% (n = 72) ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

Persistently low lymphocyte counts after FCR therapy for chronic lymphocytic leukemia are associated with longer overall survival

Joffe

Arad

Bairey

et al. 2017

Hematological Oncology

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Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis (<4.0 × 10 cells/μL) or better after FCR. Absolute lymphocyte counts were recorded at 3-, 6-, 9-, and 12-month posttreatment and correlated with overall survival (OS) and event-free survival (EFS). For each time point, analyses were limited to patients without lymphocytosis, so as to avoid possible biases from undocumented disease progressions. Lymphopenia (ALC < 1.0 × 10 cells/μL) at 3 m after FCR (69% of patients n = 68), was associated with a longer OS (5y OS 91% vs 64%, P = .001), as were ALC ≤ 2 × 10 cells/μL at 6 m (5y OS 85% vs 48%, P = .004) and ALC ≤ 1.8 × 10 cells/μL at 9 m (5y OS 93% vs 54%, P = .009). A normal-range ALC (≤4 × 10 cells/μL) at 12 m was also associated with a 91% 5y OS. Higher ALCs (but without lymphocytosis) were associated with shorter EFS (median EFS 27 months for ALC > 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P < .0001). In conclusion, lower ALC levels in the first few months following frontline FCR therapy were associated with longer OS and EFS. Possible explanations may be that lower ALCs reflect deeper clonal suppression or protracted T depletion. Absolute lymphocyte count levels may be a cheap and widely available prognostic marker, though the added value for clinical practice is the minimal residual disease era needs to be explored.

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“…The median progression-free survival (PFS) was shorter than previously observed with full-dose FCR (28 months). Recent results from observational studies suggested that dose reductions during FCR therapy actually could result in significant loss of treatment efficacy and PFS reduction compared with full-dose FCR [29,30].…”

Section: Chemoimmunotherapymentioning

confidence: 98%

Pharmacotherapeutic Management of Chronic Lymphocytic Leukaemia in Patients with Comorbidities: New Agents, New Hope

Goede

Hallek

2015

Drugs Aging

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Chronic lymphocytic leukaemia (CLL) is mostly considered a disease of the elderly. As such, many patients present with comorbidities. Several scores allow for a qualitative and quantitative assessment of comorbidity in patients with CLL. Although our knowledge about the impact of comorbidity on outcomes in patients with CLL is still incomplete, it is becoming increasingly apparent that comorbidities could negatively interfere with CLL treatment. Recently, a number of new agents have been approved for use in patients with previously untreated CLL and comorbidities (i.e. obinutuzumab, ofatumumab), as well as in patients with previously treated or high-risk CLL (i.e. idelalisib, ibrutinib). This review discusses the role of comorbidity in patients with CLL, together with the changing treatment landscape for CLL in this patient population.

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Efficacy and safety of front-line therapy with fludarabine-cyclophosphamide-rituximab regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli CLL Study Group experience

Cited by 19 publications

References 30 publications

Low‐dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD‐FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience

Low‐dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD‐FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience

Persistently low lymphocyte counts after FCR therapy for chronic lymphocytic leukemia are associated with longer overall survival

Pharmacotherapeutic Management of Chronic Lymphocytic Leukaemia in Patients with Comorbidities: New Agents, New Hope

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