Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia.

In addition to clinical staging, a number of biomarkers predicting overall survival (OS) have been identified in chronic lymphocytic leukemia (CLL). The multiplicity of markers, limited information on their independent prognostic value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We therefore performed an analysis of 23 prognostic markers based on prospectively collected data from 1948 CLL patients participating in phase 3 trials of the German CLL Study Group to develop a comprehensive prognostic index. A multivariable Cox regression model identified 8 independent predictors of OS: sex, age, ECOG status, del(17p), del(11q), IGHV mutation status, serum ?2-microglobulin, and serum thymidine kinase. Using a weighted grading system, a prognostic index was derived that separated 4 risk categories with 5-year OS ranging from 18.7% to 95.2% and having a C-statistic of 0.75. The index stratified OS within all analyzed subgroups, including all Rai/Binet stages. The validity of the index was externally confirmed in a series of 676 newly diagnosed CLL patients from Mayo Clinic. Using this multistep process including external validation, we developed a comprehensive prognostic index with high discriminatory power and prognostic significance on the individual patient level. The studies were registered as follows: CLL1 trial (NCT00262782, http://clinicaltrials.gov), CLL4 trial (ISRCTN 75653261, http://www.controlled-trials.com), and CLL8 trial (NCT00281918, http://clinicaltrials.gov)

Chronic lymphocytic leukemia

The management of chronic lymphocytic leukemia (CLL) is currently undergoing a profound change. First, several new drugs have been approved (fludarabine, bendamustine and two monoclonal antibodies, alemtuzumab and rituximab). In addition, novel monoclonal antibodies targeting CD20, CD23, CD37 or CD40, as well as drugs designed to interfere with central pathways regulating the cell cycle, the apoptotic machinery, or the leukemic microenvironment (flavopiridol, oblimersen, ABT-263 or lenalidomide) are being tested in clinical trials. Furthermore, improved protocols using reduced-intensity allogeneic progenitor cell transplantation makes it possible to offer this procedure to more patients with CLL. Finally, new prognostic markers that may influence therapeutic decisions have been identified. This review attempts to summarize the current knowledge in this rapidly moving field

Bendamustine and its role in the treatment of unfit patients with chronic lymphocytic leukaemia: a perspective review

With a median age of 72 years at first diagnosis, chronic lymphocytic leukaemia (CLL) is a disease of the elderly. At this age, many patients cannot bear an intensive chemoimmunotherapy like fludarabine, cyclophosphamide and rituximab (FCR), and therapeutic decisions are commonly complicated by a high burden of accompanying comorbidities. Clinical trials, on the other hand, are mostly designed to include a far healthier and younger trial population, with a median age in most studies well below 70 years, leading to an insufficient reflection of clinical reality. With the introduction of new targeted therapies, treatment of CLL is currently undergoing a profound change. New compounds like ibrutinib or idelalisib have enlarged the therapeutic options in treating CLL. However, so far, these oral medications imply continuous intake by the patient, which will at some point lead to the issue of adherence in most patients. In addition, long-term experiences are largely missing. In this setting, one of the oldest chemoactive substances remains a viable option for many CLL patients and their treating physicians: bendamustine, a nitrogen-mustard derivative, has proven to be a safe and efficient agent for treatment of CLL in the first- and second-line setting. In particular, there is some evidence that the substance is relatively well tolerated in elderly and unfit patients. In this review, we summarize the current data on bendamustine in the treatment of elderly and unfit patients with CLL and aim to provide a concise analysis and outlook on the current and future role of this substance in the era of new targeted agents

Obinutuzumab in chronic lymphocytic leukemia: design, development and place in therapy

For decades, treatment of chronic lymphocytic leukemia (CLL) has been based on chemotherapy. This changed when the first CD20 antibody rituximab was introduced. Since 2008, the combination of chemotherapy and CD20 antibodies has become the standard of care for most patients, and a significant fraction of patients had very long-lasting remissions after chemoimmunotherapy. Despite the improvement of response rates and overall survival (OS) by the use of chemoimmunotherapy, most CLL patients will relapse eventually. One approach to achieve more durable responses was the development of obinutuzumab (GA101), a new type of CD20 antibody that has unique molecular and functional characteristics. Obinutuzumab is a type II fully humanized CD20 antibody that binds to a partly different epitope of the CD20 protein than rituximab and due to its glycoengineered design induces greater antibody-dependent cell-mediated cytotoxicity (ADCC). Initial preclinical observations of a more effective B-cell depletion have been successfully reproduced in clinical trials with CLL patients. This review summarizes results of preclinical as well as clinical studies with obinutuzumab and provides an outlook on its future role in the therapy of CLL

Similar outcome after allogeneic stem cell transplantation with a modified FLAMSA conditioning protocol substituting 4 Gy TBI with treosulfan in an elderly population with high-risk AML

The fludarabine, amsacrine, and cytarabine (FLAMSA)-reduced-intensity conditioning (RIC) protocol has been described to be effective in patients with high-risk and refractory acute myeloic leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (aSCT). To increase safety and tolerability of the conditioning, we previously reported the feasibility to substitute the TBI component by treosulfan in elderly AML patients. We now present long-term follow-up data on patients treated with FLAMSA/treosulfan compared to the original FLAMSA/4Gy TBI protocol. We retrospectively analyzed 130 consecutive patients with high-risk or relapsed AML after aSCT following FLAMSA conditioning at our center. Fifty-eight patients were treated with FLAMSA/treosulfan due to age and/or comorbidities. Seventy-two patients were treated with FLAMSA/TBI. Median age of patients treated with FLAMSA/treosulfan was 60 years compared to 46 years in those treated with FLAMSA/TBI. The cumulative incidence of a non-relapse mortality at 4 years was 28% in FLAMSA/treosulfan patients as compared to 13% in FLAMSA/TBI. Cumulative incidence of relapse was higher in patients treated with FLAMSA/TBI (46 vs. 32%). This difference was even more prominent for patients treated in blast persistence prior to transplant (relapse incidence 70% for TBI vs. 35% for treosulfan). The overall and relapse-free survival rates at 4 years were 47 and 41%, respectively, for patients treated with FLAMSA/TBI as compared to 43 and 40% in patients treated with FLAMSA/treosulfan. These data indicate an anti-leukemic activity by FLAMSA/treosulfan especially in patients with a blast persistence prior to transplant. Older age was an independent factor for a higher non-relapse mortality. Translating FLAMSA/treosulfan to younger patients, a lower non-relapse mortality, and an improved anti-leukemic activity might add up to improved overall survival. Randomized studies are required to demonstrate an improved efficacy of treosulfan- versus TBI-based FLAMSA conditioning

The CLL12 trial protocol: a placebo-controlled double-blind Phase III study of ibrutinib in the treatment of early-stage chronic lymphocytic leukemia patients with risk of early disease progression

Observation (watch and wait) is the standard of care for patients with asymptomatic Binet stage A chronic lymphocytic leukemia (CLL). However, the clinical course of these patients is very heterogeneous with some patients requiring treatment rather soon and others not progressing for ages. The clinical staging does not reflect this high variability of the clinical course of CLL. Published data demonstrate that the comprehensive use of several risk factors dramatically improves the accuracy of prognostication independent of clinical stage. The treatment of CLL underwent considerable changes with the introduction of kinase-inhibitors, including ibrutinib, an orally administered, well-tolerated and potent inhibitor of Bruton's tyrosine kinase. This is the first prospective, multicenter, placebo-controlled, double-blind, Phase III study to compare efficacy and safety of ibrutinib to a watch-and-wait approach in Binet stage A CLL with risk of disease progression defined by the comprehensive CLL score