Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia. Krohem B-Cll 2017

Abstract

Recent developments in the diagnosis and treatment of chronic lymphocytic leukemia (B-CLL) have led to change of approach in clinical practice. New treatments have been approved based on the results of randomized multicenter trials for first line and for salvage therapy, and the results of numerous ongoing clinical trials are permanently providing new answers and further refining of therapeutic strategies. This is paralleled by substantial increase in understanding the disease genetics due to major advances in the next generation sequencing (NGS) technology. We define current position of the Croatian Cooperative Group for Hematologic Disease on diagnosis and treatment of CLL in the transition from chemo-immunotherapy paradigm into a new one that is based on new diagnostic stratification and unprecedented therapeutic results of B-cell receptor inhibitors (BRI) and Bcl-2 antagonists. This is a rapidly evolving field as a great number of ongoing clinical trials con-stantly accumulate and provide new knowledge. We believe that novel therapy research including genomic diagnosis is likely to offer new options that will eventually lead to time limited therapies without chemotherapy and more effective clinical care for B-CLL based on individualized precision medicine.

Keywords: Chronic lymphocytic leukemia; Croatia; KROHEM*; Practice guidelines as topic; Precision medicine.

Fig. 1

Flow chart describing B-CLL diagnosis and treatment 2017 paradigm shift. This chart shows diagnostics based decision steps (orange rectangles) and their sequence (orange arrows), currently approved therapies by EMA (in 2/2017) (blue rectangles), as well as the sequence for first-line treatment (green arrows) and salvage treatment lines (blue arrows). The minority of patients (about 10%) present with indication for treatment at diagnosis, while the majority are observed until the criteria for treatment are met. This part (framed) did not change. When the indication is present, B-CLL patients are eligible for first-line treatment. In this part, major changes have occurred because of recent approval of new options. Ibrutinib monotherapy is approved as continuous treatment of undetermined duration or until progression or unmanageable toxicity for all patient strata because of favorable efficacy/tolerance ratio in disease control. This is a new approved option, so that ibrutinib could be used to start the new path. In case of progression or toxicity, patients qualify for second-line treatment (approved option is venetoclax). If this fails, the patient is eligible for experimental treatments (combinations of novel agents with immunotherapy, allogeneic stem cell transplantation, CAR-T cell therapy, and the like). Theoretically, all of these could be done without further diagnostics and stratification, while avoiding chemotherapy. However, head-to-head comparison data between novel agents and chemo-immunotherapy (CIT) are still lacking. CIT, although associated with higher short- and long-term toxicities, has proved to be highly effective in achieving long, durable remissions and perhaps even a cure in some patient subsets. It was therefore in the CIT era essential to identify those who would respond, and a number of predicting factors have emerged in this setting. The NGS has revealed that intratumoral heterogeneity and genomic changes can be used for better CIT response prediction. Most important for CIT clinical use are two predictors, del(17p)/TP53mut and IGHV mutation status. The former can identify patient subset in which chemotherapy is ineffective and even contraindicated because of inducing adverse clonal evolution, and the latter can identify disease type, where patients with unmutated IGHV poorly respond to CIT and even if they respond, the response is short and clones that are more resistant emerge. Both predictors are considered standard minimum for stratification. If adverse features are present, the patients should be treated with ibrutinib or idelalisib in first line. Others may continue towards CIT that is tailored according to age and comorbidities. Fit patients qualify for FCR, unfit for Clb+Obi or like, and patients ‘in-between’ for BR. If they relapse late, the CIT may be repeated, tailored to current fitness, while early relapsed/refractory patients qualify for BRI or venetoclax salvage. At present, baseline stratification based on genetically defined risk, as well as on age and comorbidities to tailor treatment intensity is still needed for CIT, although fitness is currently not important for novel agents. The current CIT based paradigm (shown horizontally) is losing importance and the new paradigm (shown vertically) is likely to take over. However, it will require identification of new important predictors along the new path, since the majority of predictors identified for CIT lose their power in the new setting. As data accumulate, new predictors will emerge for this setting. High throughput NGS has begun to identify new predictors for targeted therapy response, as well as new predictors of failure at molecular level, as treatment proceeds. All this may eventually lead to a new upfront stratification for risk adapted precision medicine therapy in B-CLL. The ongoing trials and head-to-head comparison of novel agents and their combinations with immunotherapy versus CIT are under way. They will hopefully resolve current dilemmas. Novel therapy research including genomic diagnostics is likely to offer new options that will eventually lead to time limited therapies, without chemotherapy. Dg = diagnosis; WW(I) = watch and wait (investigate); Ind = indications for treatment; PF = predictive factors; Late R = late relapse; Early R/R = early relapsing or refractory; IBR = ibrutinib; IDELA = idelalisib; VEN = venetoclax; Exp = experimental treatment; CIT = chemo-immunotherapy