NetBIALB-cell chronic lymphocytic leukemia (B-CLL) is the most common subtype of mature B-cell neoplasms with the overall age-standardized incidence rate equal to approx. 4 per 100 000 per year. The incidence increases rapidly with increasing age. About 70% of all CLL cases is diagnosed in the population aged 65 and over. The disorder is more common in men with a male to female ratio of approximately 1,5 : 1,1. The median survival at diagnosis varies between 1 and more than 10 years.

Many people with B-CLL do not have any symptoms when it is diagnosed. A few studies demonstrated that treatment of patients with early-stage disease does not prolong survival. Thus, the standard treatment of patients with early disease is a watch-and-wait strategy, while progressive or symptomatic disease requires therapy.

A few therapy options are currently available for symptomatic, progressive B-CLL. Usually chemotherapy or chemo / immunotherapy is applied that make use of alcylating agents (e.g. chlorambucil, bendamustine), purine nucleoside analogues (e.g. fludarabine), and / or monoclonal antibodies (e.g. alemntuzumab, rituximab) either in a monotherapy or in a combination therapy.

Efficacies of some of these treatments have been compared directly in the randomized control trials (RCTs) in terms of: the partial, complete and overall remission, the progression-free survival time (PFS) and / or overall survival (OS). However, the available data are sparse, often conflicting, and most of the therapy options have not been compared directly.

The course of B-CLL and patients response to treatment is very diverse, which make it difficult to select the most appropriate therapy option and to predict progression of the disease. While deciding about initiation of the treatment and selecting the most appropriate one from all the available schemes such parameters should be taken into consideration like: stage of the disease, the overall patient’s condition, prognostic factors, patient’s age and sex, etc. It should be also considered that in case of a relapse of the disease, which is likely in most of the patients, even though the first line treatment led to a remission, the effectiveness of the subsequent lines of treatment is often lower due to growth of the population of cells immune to the treatment.

The Nalecz Institute of Biocybernetics and Biomedical Engineering PAS in cooperation with the Clinic of Hemato-oncology and Bone Marrow Transplantation Medical University of Lublin developed and implemented a few years ago a stand-alone computer system for monitoring patients with B-CLL (BIAL). The BIAL system made it possible to collect a wide range of parameters, including those that are not routinely collected. These data were intended to be used to assess an influence of the applied treatment, including the experimental immunotherapy, on patient’s state and progression of the disease.

Based on the experience gained during an implementation of the BIAL system a need was addressed to develop a new IT system NetBIAL that should make it possible to collect, in relatively short time, a large data set originating from patients treated in many national medical centers, containing smaller group of parameters but monitored in majority of the patients with B-CLL. According to the assumptions that were made, the literature review supplemented with an analysis of the data gathered in the NetBIAL data base should enable to elaborate analytical tools for a prediction of the patient’s state and outcome of the applied treatment as well as a selection of the most appropriate therapy option.

Aim of the project covers:
  • development, implementation and release of a network computer application for complex multicenter, long-term monitoring of the diagnosis, observation and treatment of patients with the B-cell chronic lymphocytic leukemia (B-CLL),
  • collection of large data set concerning patients with B-CLL and containing prognostic parameters as well as parameters characterizing patient’s state, course and outcome of the applied treatment,
  • an attempt to develop analytical tools to analyze the gathered data, facilitating: selection of the most effective treatment, assessment of the patient’s state and prediction of the disease progression.

During the first stage of the project in years 2010-2011, a multicenter data base of patients with B-CLL was developed together with a web-based application that enabled gathering of the data and facilitated an assessment of patient’s state and the course of the treatment, under the common name – NetBIAL system.

The NetBIAL system was implemented according to the requirements of the Inspector General for the Protection of Personal Data (GIODO) concerning the sensitive data sets (e.g. containing the data related to one’s health status). The NetBIAL system was registered in the registry of personal data sets kept by GIODO under the name “Data base of patients with chronic lymphocytic leukemia (NetBIAL)” and it was released for the use to medical partners of the project.

Currently the NetBIAL system is used for the centralized gathering of the data originating from a dozen or so Polish medical centers, in which patients with B-CLL are treated. Until Jan 1st, 2014 in the NetBIAL data base 874 patients were registered, including the data concerning 1635 started treatment lines.

The user interface of NetBIAL’s data access application was designed in such a way that reflects the procedure that the patients undergo after the diagnosis of B-CLL, i.e. determination of the patient’s state and the prognostic parameters and then usually repeating stages of: observation (monitoring), control examinations and visits, application of the selected treatment and assessment of its outcome. The system contains also a visualization module facilitating assessment of patient’s state.

An exemplary screen-shot from the NetBIAl system, showing a form concerning the applied treatment is presented below.NetBIAL formularz

In course to develop the analytical tools enabling the prognosis of patient’s state and the outcome of the applied treatment and to facilitate the selection of the most appropriate therapy option an extensive literature review was conducted regarding the chronic lymphocytic leukemia and the multi-directional Bayesian metaanalysis was performed (using the Monte-Carlo technique) to compare different B-CLL therapy options, including:

  1. simple metaanalysis of the complete, partial and overall remission for two pairs of chemotherapy agents used in therapy of B-CLL,
  2. network metaanalysis of the complete, partial and overall remission for agents used in therapy of B-CLL with an assessment of an influence of the disease stage and patient’s age on values of these parameters,
  3. network metaanalysis of the progression free survival and the overall survival applying the partial polynomials to describe parameters representing the treatment effect.

This analysis was conducted using up-to-date data analysis methods, e.g. the node-splitting method to assess the consistency of the data used in the network metaanalysis or the fractional polynomials method to describe hazard function in the survival model.

The conducted analysis led to selection of models, which approximate the results of an application of the available therapy options, generalized based on the available data, in the most accurate way. The developed models / programs can be repeatedly used in future, when results of new clinical trials are published, to verify whether the most accurate models should be updated.

The last stage of the project concerns an application of the methodology related to a development of the Bayesian network to combine results of the metaanalysis, the data collected using the NetBIAL system and the medical experts’ knowledge. It should enable to utilize information concerning a particular patient (such like: risk factors, current health status or treatment history) while predicting the disease progression and while selecting the most appropriate therapy option.

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Current list of national medical units registered in NetBIAL system:
  • Klinika Hematoonkologii i Transplantacji Szpiku UM w Lublinie
  • Klinika Hematologii Uniwersytetu Medycznego w Łodzi
  • Klinika Nowotworów Układu Chłonnego Centrum Onkologii Instytutu Marii Curie-Skłodowskiej w Warszawie
  • Klinika Hematologii IHiT w Warszawie
  • Klinika Hematologii, Onkologii i Chorób Wewnętrznych Warszawskiego Uniwersytetu Medycznego
  • Klinika Chorób Wewnętrznych i Hematologii z Ośrodkiem Transplantacji Szpiku CSK WAM w Warszawie
  • Klinika Hematologii Collegium Medicum Uniwersytetu Jagiellońskiego w Krakowie
  • Klinika Hematologii i Transplantacji Szpiku Śląskiego Uniwersytetu Medycznego w Katowicach
  • Klinika Chemioterapii Onkologicznej z pododdziałem leczenia chłoniaków Śląskiego Uniwersytetu Medycznego w Katowicach
  • Klinika Hematologii, Nowotworów Krwi i Transplantacji Szpiku Akademii Medycznej we Wrocławiu
  • Klinika Hematologii i Chorób Rozrostowych Układu Krwiotwórczego Uniwersytetu Medycznego w Poznaniu
  • Klinika Hematologii i Transplantologii Gdańskiego Uniwersytetu Medycznego
  • Klinika Hematologii Pomorskiego Uniwersytetu Medycznego w Szczecinie
  • Oddział Wewnętrzny i Hematologii Wielospecjalistycznego Szpitala Miejskiego im. Józefa Strusia w Poznaniu
  • Oddział Hematologii i Chorób Rozrostowych Układu Krwiotwórczego Szpitala Uniwersyteckiego w Bydgoszczy
  • Oddział Hematologii i Chorób Wewnętrznych Wojewódzkiego Szpitala Specjalistycznego im. L. Rydygiera w Krakowie
  • Oddział Hematologii Onkologicznej Szpitala Specjalistycznego Podkarpackiego Ośrodka Onkologicznego w Brzozowie
  • Dział Hematologii Świętokrzyskiego Centrum Onkologii w Kielcach
  • Oddział Hematologii Wojewódzkiego Szpitala Specjalistycznego im. Fryderyka Chopina w Rzeszowie
  • Oddział Hematologii Specjalistycznego Szpitala Miejskiego w Toruniu
  • Oddział Hematologiczny Zamojskiego Szpitala Niepublicznego w Zamościu

This list can be extended to include additional medical units, which treat patients with B-CLL and which expressed their interest to participate in the project.