Changing paradigms in the treatment of chronic lymphocytic leukemia

Foon, Kenneth A.; Hallek, Michael

doi:10.1038/leu.2009.266

Cited by 17 publications

(16 citation statements)

References 99 publications

(103 reference statements)

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“…1 In an attempt to reduce the neutropenia and maintain the high response rate of standard-dose FCR, we conducted a prospective phase 2 clinical trial in untreated CLL patients using lower doses of FC and higher dose of R followed by R maintenance until progression or up to 2 years (FCR-Lite). Details of the study were previously described.…”

Section: Long-term Results Of Chemoimmunotherapy With Low-dose Fludarmentioning

confidence: 99%

Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia

Foon¹,

Mehta

Lentzsch

et al. 2012

Blood

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Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemiaChemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) is currently considered the gold standard first-line therapy for chronic lymphocytic leukemia (CLL). 1 In an attempt to reduce the neutropenia and maintain the high response rate of standard-dose FCR, we conducted a prospective phase 2 clinical trial in untreated CLL patients using lower doses of FC and higher dose of R followed by R maintenance until progression or up to 2 years (FCR-Lite). Details of the study were previously described. (73%) achieved complete response (CR), 2 (3%) achieved nodular partial remission (nPR), 11 (17%) achieved partial remission (PR), and 4 (6%) did not respond. Among the 50 patients with Rai stage I-II there were 38 (76%) CRs and 10 (20%) PRs and among the 13 patients with Rai stage III-IV there were 8 (62%) CRs and 3 (23%) PRs. For patients Ͻ 60 years there were 35 (81%) CRs and 5 (12%) PRs, for patients between 60-69 years there were 6 (55%) CRs and 4 (36%) PRs, and for patients Ն 70 years there were 5 (56%) CRs and 4 (44%) PRs. For the 40 patients with normal cytogenetics, del13q or ϩ12 there were 31 (78%) CRs, 7 (17%) PRs, and 2 (5%) NRs. Eight of 9 (89%) patients with del11q had a CR and 1 (11%) had a PR. Three of 3 patients with del17p had PRs.The median overall survival has not been reached and the median progression-free survival was 5.8 years and the 3-and 5-year progression-free survival probability is shown in Table 1. This compares favorably with the MD Anderson Cancer Center (MDACC) phase 2 FCR trial where the 6-year actuarial OS and failure-free survival were 77% and 51%, respectively, as well as the FCR arm of the German CLL Study Group GCLLSG) where the PFS was 4.4 years. [4][5][6] Fifty-five patients (85%) completed all 6 courses of FCR-Lite with dose reduction in 2% of total cycles. Grade 3-4 neutropenia occurred in 11% of total cycles of FCR-Lite and grade 3-4 infections were seen in 6% of patients. Three patients developed myelodysplastic syndromes and 2 patients developed B-cell lymphomas after FCR-Lite therapy.In summary, the FCR-Lite regimen represents an active frontline treatment with excellent responses and duration of response with a favorable toxicity profile. Interpretation of these data and comparisons with the MDACC and GCLLSG trials should be viewed in light of the relatively low numbers of patients, relatively early Rai stages of the patients, use of prophylactic growth factors, and maintenance rituximab in the FCR-Lite trial. Further studies with FCR-Lite will include combination therapies with promising new agents.

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Section: Long-term Results Of Chemoimmunotherapy With Low-dose Fludarmentioning

confidence: 99%

Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia

Foon¹,

Mehta

Lentzsch

et al. 2012

Blood

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“…When chlorambucil, which is among the oldest drugs used for the treatment of CLL, 3 was compared with bendamustine for efficacy and toxicity profiles, the overall response rate to bendamustine was 68%, which was more than double the observed rate with chlorambucil. 4 Based on these results, bendamustine was approved by the US Food and Drug Administration for the treatment of CLL.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of bendamustine in combination with fludarabine in primary chronic lymphocytic leukemia cells

El-Mabhouh¹,

Ayres²,

Shpall³

et al. 2014

Blood

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Key Points• The fludarabine and bendamustine combination is cytotoxic to CLL cells even in the presence of a protective microenvironment.• H2AX activation was maximum with the combination, and unscheduled DNA synthesis induced by bendamustine was blocked by fludarabine.The fludarabine and cyclophosphamide couplet has become the backbone of the chronic lymphocytic leukemia (CLL) standard of care. Although this is an effective treatment, it results in untoward toxicity. Bendamustine is a newly approved and better-tolerated alkylating agent. We hypothesized that similar to cyclophosphamide, bendamustineinduced DNA damage will be inhibited by fludarabine, resulting in increased cytotoxicity.To test this hypothesis and the role of the stromal microenvironment in this process, we treated CLL lymphocytes in vitro with each drug alone and in combination. Simultaneous or prior addition of fludarabine to bendamustine resulted in maximum cytotoxicity assayed by 3,39-dihexyloxacarbocyanine iodine negativity, annexin positivity, and poly (adenosine 59-diphosphate-ribose) polymerase cleavage. Cytotoxicity elicited by combination of both agents was similar in these malignant B cells cultured either in suspension or on marrow stroma cells. Cell death was associated with DNA damage response, which was determined by phosphorylation of H2AX and unscheduled DNA synthesis. H2AX activation was maximum with the drug combination, and unscheduled DNA synthesis induced by bendamustine was blocked by fludarabine. In parallel, ATM, Chk2, and p53 were phosphorylated and PUMA was induced. Cell death was caspase independent; however, caspases did decrease levels of Mcl-1 survival protein. These data provide a rationale for combining fludarabine with bendamustine for patients with CLL. (Blood. 2014;123(24):3780-3789) IntroductionThe most efficacious therapies in chronic lymphocytic leukemia (CLL) include alkylating agents and the combination of these DNA-damaging drugs with purine nucleoside analogs. In fact, the combination of cyclophosphamide and fludarabine or pentostatin has long been the standard of care for CLL.Bendamustine is a newly approved alkylating agent. Chemically, bendamustine is 4-{5-[bis(2-chloroethyl)amino]-1-methyl-2-bezimidazolyl} butyric acid hydrochloride.1 Structurally, it is an alkylating agent with a benzimidazole ring and a butyric acid side chain, which improves water solubility.2 The nitrogen mustard group of bendamustine resembles a similar group on chlorambucil and cyclophosphamide, the 2 most commonly used alkylating agents for CLL.When chlorambucil, which is among the oldest drugs used for the treatment of CLL, 3 was compared with bendamustine for efficacy and toxicity profiles, the overall response rate to bendamustine was 68%, which was more than double the observed rate with chlorambucil. 4 Based on these results, bendamustine was approved by the US Food and Drug Administration for the treatment of CLL. 5 In another randomized clinical study of untreated CLL, fludarabine resulted in higher response rates and ...

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“…Choice of initial therapy is based on several factors, including individual patient characteristics, prognostic markers, disease burden, and the rate of disease progression [Foon and Hallek, 2010]. In recent years, a deeper understanding of CLL and the introduction of purine analogues and anti-CD20 monoclonal antibodies as treatment options have switched the focus of management from a palliative approach to one directed at improving progression-free survival (PFS) and overall survival [Gribben, 2010;Foon and Hallek, 2010].…”

Section: Introductionmentioning

confidence: 99%

“…Although allogeneic stem-cell transplantation has been shown to provide a durable response in select patients with CLL [Dreger et al 2010;Gribben et al 2005], many patients with CLL are considered poor candidates for allogeneic stemcell transplantation due to age, comorbidities, and vulnerability to treatment-related toxicities [Hallek, 2009;Gribben et al 2005]; thus, for many patients, the disease remains incurable with a highly variable clinical course [Gribben, 2010;Foon and Hallek, 2010]. Many patients remain asymptomatic for years and face a lengthy disease course .…”

Section: Introductionmentioning

confidence: 99%

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Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study

Kolibaba

Sterchele

Joshi

et al. 2013

Therapeutic Advances in Hematology

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Objectives: Bendamustine is a unique cytotoxic agent active against various human malignancies, including chronic lymphocytic leukemia (CLL). In vitro studies suggest that cytotoxic activity of bendamustine on CLL-derived cells is synergized by rituximab. A retrospective chart review was conducted to characterize treatment-naïve outpatients and those with relapsed disease aged 70 years and over with CLL receiving bendamustine (with or without rituximab) and to evaluate real-world patterns of care, safety, and effectiveness. Methods: Using McKesson Specialty Care/US Oncology Network iKnowMed databases, 91 outpatients with at least two recorded visits and at least two cycles of bendamustine monotherapy or bendamustine-rituximab combination therapy were identified and included. Mean age at diagnosis and start of first therapy was 70.3 and 77.4 years respectively, and 63.7% of patients were men. Results: Observed overall response rate was 56.3% in pooled treatment-naïve patients [n = 9; complete response (CR) 18.8%; partial response (PR) 37.5%; nodular partial response (nPR) 0%] and 58.7% in pooled patients with relapsed disease (n = 44; CR 13.3%; PR 44.0%; nPR 1.3%). Median time to progressive disease has not been reached for the 16 treatment-naïve patients (median follow up 15.1 months), and was 18.4 months for those with relapsed disease (n = 73). No unexpected toxicities were observed. Overall rate of blood/bone marrow toxicities (all grades) was 40.7%; grade 3/4 rates were 18.8% in treatment-naïve patients and 25.3% in those with relapsed disease. Most frequent nonhematologic adverse events were fatigue and rash. Conclusion: In this retrospective chart review of 91 outpatients with CLL aged 70 years and over, bendamustine (with or without rituximab) was an effective therapeutic option with manageable toxicity.

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Changing paradigms in the treatment of chronic lymphocytic leukemia

Cited by 17 publications

References 99 publications

Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia

Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia

Evaluation of bendamustine in combination with fludarabine in primary chronic lymphocytic leukemia cells

Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study

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