Subcutaneous Alemtuzumab in Fludarabine-Refractory Chronic Lymphocytic Leukemia: Clinical Results and Prognostic Marker Analyses From the CLL2H Study of the German Chronic Lymphocytic Leukemia Study Group

Stilgenbauer, Stephan; Zenz, Thorsten; Winkler, Dirk; Bühler, Andreas; Schlenk, Richard F.; Groner, Silja; Busch, Raymonde; Hensel, Manfred; Dührsen, Ulrich; Finke, Jürgen; Dreger, Peter; Jäger, Ulrich; Lengfelder, Eva; Hohloch, Karin; Söling, Ulrike; Schlag, Rudolf; Kneba, Michael; Hallek, Michael; Döhner, Hartmut

doi:10.1200/jco.2008.21.1128

Cited by 246 publications

(167 citation statements)

References 37 publications

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“…The OR for all patients was 62%. This rate was comparable with that achieved in pretreated patients within the REACH trial with the FCR regimen and with FC plus alemtuzumab (OR: 69.9% and 67%, respectively) [27,28], and higher than that reported for alemtuzumab monotherapy (OR: 34%) [5]. It is noteworthy that the REACH trial did not include fludarabinerefractory patients, and the 17p deletion was present in only 7% of the patients.…”

Section: Discussionsupporting

confidence: 72%

“…17p and 11q deletions are found in around 5% and 20% of cases at diagnosis (de novo deletions), respectively, but can also be acquired during the evolution of the disease. Indeed, the incidence of 17p-in patients with relapsed or refractory CLL can be up to 30% [5].…”

Section: Introductionmentioning

confidence: 99%

“…The overall response rate (OR) to the anti-CD52 antibody alemtuzumab in the relapsed setting was 34%, with OR of 39% in patients with 17p-, 30% in patients with 11q-, and a median progression-free survival (PFS) of 7.7 months [5]. The majority of responses are only partial, particularly in patients with bulky lymphadenopathy, with a high burden of opportunistic infections.…”

Section: Introductionmentioning

confidence: 99%

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The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

et al. 2013

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Treatment of patients with B-cell chronic lymphocytic leukemia (CLL) relapsed/refractory (R/R) to conventional treatments is particularly challenging. The combination of bendamustine and cytarabine has demonstrated distinct and synergistic mechanisms of action in preclinical studies on cell lines and primary tumor cells of several B-cell lymphomas, including 17p deleted or TP53 mutated CLL. The efficacy of rituximab (375 mg/m 2 , Day 1), plus bendamustine (70 mg/m 2 , days 1-2), and cytarabine (800 mg/m 2 , Day 1-3; R-BAC), every 28 days for up to four courses, was evaluated in a pilot trial enrolling 13 patients with very selected high-risk R/R CLL. All patients (median age 60 years, range 53-74) had symptomatic Binet stage B or C active disease requiring treatment, were characterized by adverse cytogenetics (17p deletion, 11q deletion, or both), unmutated immunoglobulin heavy-chain variable region, and were heavily pretreated (1-5, median three previous lines). Overall, R-BAC was well tolerated with limited non-hematological toxicity. Major toxicities were transient Grade 3/4 neutropenia and thrombocytopenia in 84% and 85% of patients, respectively. Overall response rate (OR) was 84%, including complete and partial response in 38% and 46% of patients, respectively. Patients with 17p deletion had an OR of 78%. After a median follow-up of 17 months, median progression-free survival was 16 months while median overall survival (OS) was not reached (1-year OS: 75 6 13%). R-BAC is an active regimen in R/R heavily pretreated high-risk patients with CLL, representing an option for the treatment of patients that are usually refractory to standard therapy. Am. J.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

et al. 2013

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“…Efficiency was the same in all genetic subgroups, notably in 17p-and 11q-deletion, TP53 mutation and unmutated IGHV status (Fig. 4) [14].…”

Section: Alemtuzumabmentioning

confidence: 80%

Refractory chronic lymphocytic leukemia - new therapeutic strategies

Schnaiter

Stilgenbauer

2010

Oncotarget

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AbstrAct:Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy. Nevertheless, refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis. Important risk factors are 17p deletion and/or mutation of TP53. For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved. Meanwhile we have to face also refractoriness to alemtuzumab. Importantly, the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL. The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor. Further B-cell antigens are targeted by lumiliximab (CD23), TRU-016 (CD37) and blinatumomab (CD19). Apart from monoclonal antibody therapies, a great number of small molecules are examined for the treatment of refractory and relapsed CLL. Most of these agents aim to overcome apoptosis resistance in CLL cells or influence the microenvironment. Typical targets are regulators of the cell cycle and antiapoptotic molecules like the members of the Bcl-2 family. Up to now the most promising agents appear to be flavopiridol and lenalidomide among others.

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“…The phase II GCLLSG CLL2H trial evaluated the safety and efficacy of subcutaneous alemtuzumab in patients with fludarabine-refractory CLL, and reported that OR was 34% (4% CR and 30% PR), median PFS was 7.7 months, and median OS was 19.1 months [56]. Efficacy did not vary significantly between genetic subgroups, indicating that alemtuzumab treatment could overcome the adverse prognostic impact of IGHV mutation status, TP53 mutation, and genomic aberrations.…”

Section: Clanahan Et Al Treatment Of Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Current strategies for the diagnosis and management of chronic lymphocytic leukemia (CLL), with a focus on poor-risk CLL: A review

Clanahan¹,

Dreger

2011

Turk J Hematol

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Despite substantial advancement in the understanding and treatment of chronic lymphocytic leukemia (CLL), a standard curative approach does not exist. The choice of treatment is generally based on the existence of biological and genetic factors associated with the prediction of prognosis, individual response to therapy, and duration of remission. About 20% of patients that require treatment have an aggressive disease course and die within a few years, despite early initiation of intensive therapy (poor-risk CLL). Poor-risk CLL can be predicted by the presence of genomic markers, and the quality and duration of response to purine-analogue-based treatment. Within this patient subgroup alternative treatment approaches such as alemtuzumab or new substances such as flavopiridol or IMiDs® should be considered. To date, the only treatment bearing curative potential is allogeneic stem cell transplantation; in contrast to conventional immunochemotherapy, it can provide long-term disease control, even in patients with del 17p or other unfavorable biological and clinical risk factors. The aim of this review was to outline the current strategies for the diagnosis and management of CLL, with a focus on high-risk CLL. (Turk J Hematol 2011; 28: 86-96) Key words: CLL, genetics, poor-risk, treatment, allogeneic stem cell transplantation Günümüzde bu hastalarda şifa sağlayıcı potansiyele sahip tek tedavi seçeneği allogeneik kök hücre naklidir. Bu yöntemle, geleneksel immünokemoterapinin aksine, del 17p veya diğer olumsuz biyolojik ve klinik risk faktörlerine sahip hastalarda bile hastalığın uzun süreli denetimi sağlanabilir. Bu derleyici incelemede, yüksek riskli KLL'ye odaklanarak KLL tanı ve tedavisine ilişkin güncel stratejilerin özetlenmesi amaçlanmıştır. (Turk J Hematol 2011; 28: 86-96)

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Subcutaneous Alemtuzumab in Fludarabine-Refractory Chronic Lymphocytic Leukemia: Clinical Results and Prognostic Marker Analyses From the CLL2H Study of the German Chronic Lymphocytic Leukemia Study Group

Cited by 246 publications

References 37 publications

The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high‐risk patients with chronic lymphocytic leukemia

Refractory chronic lymphocytic leukemia - new therapeutic strategies

Current strategies for the diagnosis and management of chronic lymphocytic leukemia (CLL), with a focus on poor-risk CLL: A review

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