Research Paper on Treatment of Chronic Lymphocytic Leukemia Patients

Introduction

There is many transformations happening in the treatment of chronic lymphocytic leukemia (CLL) patients. The transformation is now driven by the emergence of new methods of therapy. Some of the emerging methods include kinase inhibitors, which normally aim at achieving crucial survival as well as proliferation signals. Specifically, this modality targets the B cell receptor (BCR) signaling. It also targets the development of important monoclonal antibodies that are normally directed towards the critical surface molecules. It is also vital to understand ibrutinib, formally known as PCI-32765.It is described as a selective inhibitor of Bruton's tyrosine kinase (BTK). This inhibitor usually inactivates the enzyme through irreversible covalent bonding to the Cys-481 within the ATP-binding domain of BTK.

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Notably, ibrutinib is given to patients with CLL once every day. This medicine is administered orally at a dose of 420mg. Administration of the inhibitor on patients is stopped when disease progression or toxicity takes place. It has been established that this treatment is highly responsive in patients with CLL. Specifically, treatment-naive patients have reported an overall response rate of 86%. The response rate may increase to a level of 90% among the relapsed/refractory patients when followed up. Importantly, the clinical responses to ibrutinib treatment involve speedy shrinkage of the enlarged lymph nodes and the spleen in the course of the first therapy weeks. There is also the high occurrence of increased peripheral blood leukemia cell number. It is believed that lymphocytosis takes place because of the retribution of CLL cells. This retribution takes place from the tissue compartments into peripheral blood. Reportedly, researchers have established that ibrutinib has the ability to effectively controlling BCR signaling and proliferation of leukemia cells. The inhibitor can also block the survival, migration, and adhesion of the leukemia cells in vitro.

Methodology

The purpose of this research was to study the actions of ibrutinib in CLL patients. The study was done by labeling DNA of proliferating CLL cells within vivo. This labeling was done using deuterium as shown in figure one below. From the diagram, it can be seen that subjects, CLL patients, were requested to drink heavily deuterated water for a period of four weeks. This treatment was done before the application of ibrutinib therapy. It is important to report that the determination of the effects of ibrutinib treatment on proliferation and death of leukemia cells was enabled by monitoring the production of deuterium-marked CLL tumor cells over a period of time before the start of therapy as well as the speed of dilution by the unlabeled cells after the therapeutic process. The same monitoring enabled the study of the action of ibrutinib treatment on the mobilization of the cells from lymphoid tissues, trafficking. The research also involved analysis of the volumetric alterations in the secondary lymphoid organs, especially after the onset of the ibrutinib therapy. The ones with changes in peripheral blood CLL cell number were correlated. Calculation of the rate of CLL cell death within blood and tissue was separately done using mathematical modeling. Results from this experiment are presented in this paper.

Figure One: Workflow and Experiment Outline

In the above diagram, A illustrates the process of incorporating deuterium labels into the DNA of the dividing cells, including CLL cells of patients. Diagram B illustrates the main three stages of the trial, which included labeling, resting and treatment with the ibrutinib drug. There were thirty patients, who participated in all the three stages of the experiment.

Findings

Firstly, observations were made about the CLL cell birth as well as death rates as estimated using the heavy deuterated water labeling. The mean birth rate of CLL cells was 0.39% 0.21% per day before the introduction of ibrutinib therapy. It is vital to note that this observation was made based on the appearance rate of the cells labeled in the course of the initial eight weeks just before starting ibrutinib therapy. The fraction of the deuterium-marked CLL cells was stable after the start of the ibrutinib therapy. This stability followed washout of deuterium from the body water. The ALCS increased instantly after initiation of the ibrutinib therapy. However, there was no significant alteration in the proportion of labeled cells. This developed led to a maintained plateau in the fraction of the labeled CLL cells. The finding showed that more cells within the bloodstream had not divided after ibrutinib therapy was administered. Newly divided cells would not have the deuterium labels.

It was also established that peripheral blood CLL cells decreased progressively during further ibrutinib therapy. However, the fraction of circulating CLL cells labeled using deuterium did not reduce in number in a progressive manner. This development showed that there were quite a few newly divided and unlabeled cells entering the blood circulation stream in the course of the ibrutinib therapy. The described findings are in consonance with the conceptual view that ibrutinib has a strong inhibitory impact on the proliferation of the leukemia cells. Really, the fraction of labeled CLL cells did fall at a rate of 0.05% 0.09% per day in the course of the ibrutinib treatment. It proved the slow rate at which the CLL cells, newly divided hence not labeled, were entering the blood circulation stream. It was also found out that the measured birth rate of CLL cells fell from 0.39% 0.21% to 0.05% 0.09% per day because of the ibrutinib treatment. This result again shows the strong inhibitory impact of the ibrutinib drug on the proliferation of the CLL cells. It implies that proliferation rate of the CLL cells is strongly cut down by ibrutinib treatment. The results of the study also confirm that the death rate of CLL cells increases on the administration of the ibrutinib drug. Categorically, the death rate of the CLL cells increased from a level of 0.18% 0.18% to 1.5% 0.83% per day after the ibrutinib treatment. It can be seen that there were significant changes observed in the birth and death rates of CLL cells before and after ibrutinib treatment. The changes in birth and death rates occurred rapidly, dramatically and stabilized.

Secondly, the research focused on observing the clinical responses and alterations within the peripheral blood cell number and marrow infiltration in the course of the ibrutinib therapy. The results of this study are illustrated in figure two below, which shows the clear trend in peripheral blood cell number. It also shows the rate of bone marrow infiltration. The progression-free and overall survival rate of cells during ibrutinib treatment can also be seen in figure two below.

Figure Two: Ibrutinib blocks CLL cell birth and increases death of same cells

In figure two, diagram A illustrates the deuterated heavy water enrichment data taken from the plasma of patients with CLL. This first diagram shows enrichment of the deuterated heavy water blood in the first four weeks of deuterium ingestion. It illustrates the dilution that took place during the washout stage. The procedure seen in diagram A is in line with the tenets of the exponential decay model. The diagram shows that the percentage of the deuterium enrichment within the DNA of the peripheral blood CLL cells was measured and turned into a fraction of newly divided cells. In this diagram, data for the first twelve weeks is plotted. This data contains that of the labeling and washout phases. Diagram C shows the plateau within the proportion of labeled CLL cells after the start of the ibrutinib treatment. This observation implies the arrest of the CLL cell birth since there is the absence of dilution in the fraction of the previously divided and labeled CLL cells. There is more crucial information from the study on diagram D. This specific diagram indicates the rise in ALC before the administration of the ibrutinib drug, which is as a result of the higher birth than death rates. In diagram E, it can be seen that after the start of the ibrutinib therapy, ALC rises initially but for a brief moment. This initial brief rise of the ALC is as a result of the redistribution lymphocytosis. It starts to decline steadily and continuously with the strong impact of the ibrutinib drug. It can be seen in diagram F that the calculated birth and death rates of CLL cells before and after application of ibrutinib therapy prove the strong inhibitory effect of the drug. The drug is able to inhibit proliferation of the CLL cells and accelerate the death rate of the CLL cells. This development causes ACL clearance.

Fig. Three: Peripheral blood cell counts, bone marrow infiltration, and survival during ibrutinib treatment

The above diagram illustrates the death rates of CLL cells as estimated using computational modeling. A indicates the ALC before and after beginning the therapy. In essence the redistribution lymphocytosis was only visible in patients with mutated IGHV. Redistribution lymphocytosis did not happen in patients with unmutated IGHV.

Fig. Four: Volumetric analyses of CLL lymph node and spleen manifestation

The above figure shows developments before and two months after start of the ibrutinib therapy. The color green indicates axillary, blue shows mesenteric, red is for other intra-abdominal while orange stand for spleen. The volumes of disease sites are displayed near each involved part.

Discussion

The data presented above clearly show directly in vivo within the CLL patients that ibrutinib drug has got strong, immediate and rapid impacts on the CLL cells. It curbs the proliferation of these cells and accelerates their death rate. It is worth discussing that the initial lymphocytosis is not a function of CL cell proliferation. The researcher made interesting observations from the whole study. It has been documented for a long time that Leukemia has no cure. Many scientists and healthcare practitioners regard Leukemia as a killer cancer, which can only be prevented but not killed, once it has inhabited a human being. However, this study brings immense hope to the healthcare industry since it empirically proves the curing action of the ibrutinib drug.

Initially, chronic lymphocytic leukemia was seen as simply a homogeneous disease of the B cells, which was minimally self-renewing. People thought that CLL relentlessly increased as a result of the faulty apoptotic mechanism. However, this view has since changed and CLL is now viewed as a heterogeneous disease. It originates from the antigen-stimulated mature B lymphocytes that evade death through interceding external signals. Alternatively, they die through apoptosis and then replenish as a result of proliferating precursor cells. It is also now well known that the B lymphocytes usually mature in the bone marrow, where they also rearrange the immunoglobulin variable (V) gene parts.This rearrangement is what creates the code for the immunoglobulin molecule, which then operates as the B-cell antigen receptor.

In the current study, the CLL birth rate decreased from 0.39% per day prior to the ibrutinib treatment to 0.05% per day after the therapy. This important result was evident in the high level of stability within the fraction of deuterium-marked CLL cells as detected within the blood after the ibrutinib treatment was administered and deuterated heavy water had washed out of the pool of body water. Expectedly, the dilution of the deuterium-labeled CLL cells by the unlabeled ones would happen if there was more birth of new CLL cells. This case was true among the untreated CLL patie...