Role and timing of new drugs in CLL

Signaling through the B-cell receptor (BCR) has emerged as a potential key mechanism in CLL pathogenesis. It has been suggested that the BCR may induce antigen-independent cell-autonomous signaling in CLL.1 The importance of BCR signaling for CLL pathogenesis is underscored by the prognostic value of the IGVH mutational status2 or the restricted repertoire of IGVH gene usage (stereotypy).3 In addition, the use of whole exome sequencing and large, annotated clinical CLL databases has allowed describing the genomic landscape in CLL. Recurrent mutational patterns suggest that BCR and inflammatory pathways, NOTCH signaling, Wnt signaling, DNA damage control, chromatin modification, and RNA and ribosomal processing are frequently altered in CLL.4 In addition, the interaction of CLL cells with their microenvironment is essential for CLL pathogenesis. In knock-out models, leukemia-associated macrophages were shown to be important components of the microenvironment of CLL cells.5 Even conventional therapeutics such as chemotherapy with alkylators and monoclonal antibodies mediate their effects trough compartment-restricted interactions with macrophages.6 Finally, agents supposed to exclusively target BCR-associated kinases such as Lyn or Bruton tyrosine kinase seem to exert essential effects through the modulation of the leukemic microenvironment, since targeted deletions of these kinases reduce the capacity of macrophages to “feed” CLL growth.7 These insights have allowed to create a strongly improved understanding of the pathogenesis of this leukemia and to establish new, less toxic principles of therapies by using kinase inhibitors or Bcl2 antagonists. The clinical course of CLL is highly variable but can be predicted today by a plethora of clinical, biological, genetic, and molecular factors.8 The challenge is to define a limited set of meaningful tests to predict the prognosis and/or response to treatment with reasonably high reliability. Therefore, we have teamed up with an international consortium of study groups to create the CLL International Prognostic Index (CLL-IPI).9 Data of 3472 treatment-naïve patients from France, Germany, UK, United States, and Poland were used, and multivariate analyses were performed using 27 baseline factors and overall survival (OS) as endpoint. Two separate datasets of 838 patients from the Mayo Clinic and 416 from a Scandinavian population-based cohort were added for external validation. Five independent prognostic factors were identified: TP53 deletion and/or mutation (collectively called TP53 dysfunction), IGHV mutational status, serum β2-microglobulin, clinical stage, and age. By using a weighted grading of the independent factors, a prognostic index was derived separating 4 risk groups with significantly different OS at 5 years (P < .001; C-statistic, c = 0.723) (See Table 1). These risk groups were confirmed by all validation datasets. The CLL-IPI also allows to propose a practical approach when treatment is indicated (Table 1). It needs to be stressed that patients at early stages or with low CLL-IPI or with asymptomatic disease do not require treatment even in the era of novel agents. Chlorambucil was the standard treatment for CLL for several decades.10-12 In the 1990s, combinations of purine analogues (fludarabine) and cyclophosphamide were found to improve the quality and duration of response in younger patients.13-15 Building from these combinations, the addition of the anti-CD20 monoclonal antibody rituximab to fludarabine and cyclophosphamide created the first CLL treatment regimen that was shown to prolong OS,16 and rituximab to fludarabine and cyclophosphamide became the standard of care for patients able to tolerate this treatment.16-18 Subsequently, the addition of a novel-humanized, glycoengineered anti-CD20 antibody obinutuzumab to chlorambucil also led to a prolonged survival in elderly patients with comorbidities.19, 20 Thus, chemoimmunotherapy using anti-CD20 monoclonal antibodies has become the standard treatment for most CLL patients, independently of age. More recently, a growing understanding of CLL pathogenesis has fostered the development of drugs targeting pathways that appear essential for leukemic cell survival. Two kinase inhibitors, ibrutinib and idelalisib, which respectively target Bruton tyrosine kinase and phosphatidylinositol-3-kinase, have demonstrated efficacy and were recently approved. While the broadest current application is in relapsed patients, these agents have specifically improved the care for patients with TP53 dysfunction in the first-line setting.21, 22 Ibrutinib is recommended as a first line therapy for all patients with a TP53 dysfunction in the absence of a contraindication. Idelalisib in combination with rituximab is recommended for patients with TP53 dysfunction not suitable for alternative first-line treatment options. Other agents targeting kinases in the BCR signalling and related pathways, as well as antibodies targeting surface antigens, such as CD37, are currently being tested in clinical trials. The BCL-2 antagonist venetoclax has recently shown an impressive therapeutic efficacy, which appears to be independent of adverse prognostic parameters, such as a TP53 dysfunction or refractoriness to fludarabine.23, 24 Venetoclax was recently approved for treatment of relapsed patients with TP53 dysfunction.24 Today, we need to create optimized therapeutic combinations to obtain long-lasting remissions, if not cure for CLL patients. One of these concepts uses sequential targeted therapies to eradicate residual disease. The treatment intensity is tailored by assessing minimal residual disease.25 First results obtained by this approach have been promising. Overall, the current recommendations for therapy have become less standardized than a few years ago. For many situations, there are multiple options, and the definitive choice depends on the comorbidity or expected toxicity profile of the drugs applied. On the basis of the current knowledge, we have proposed a treatment algorithm that is constantly updated and shown in Tables 2 and 3. By using this algorithm, the choice of the best treatment depends on the disease activity, molecular risk of the leukemia (p53 dysfunction indicating high-risk), and first-line versus second-line therapies. The choice of the best inhibitors or agents depends also on the typical side effects of some of these agents (eg, ibrutinib inducing a relative contraindication for patients with atrial fibrillation). FCR (age ≤ 65 y) BR (age > 65 y) Ibrutinib Idelalisib-rituximab (if ibrutinib therapy is not suitable because of comorbidities and/or comedication) Ibrutinib Idelalisib-rituximab (if ibrutinib is not suitable because of comorbidities and/or comedication) Like in other hematologic malignancies, the management of CLL is currently undergoing a dynamic and rapid change. Targeted and nonchemotherapeutic drugs such as obinutuzumab, ibrutinib, idelalisib, or venetoclax when used in combinations, will continue to change current treatment recommendations very dramatically. Therefore, it is important that we contribute to the impressive and historically unique chance by offering our time and commitment to include our patients into current clinical trials.