Early Treatment Prediction and Immunological Effects of Tyrosine Kinase Inhibitor Therapy in Chronic-Phase Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKIs) blocking the BCR-ABL1 oncokinase activity have led to a revolutionary progress in the treatment and prognosis of chronic myeloid leukemia (CML). Nevertheless, a small fraction of patients still does not respond satisfactorily to TKI treatment. Therefore, early prediction of treatment response remains one of the major research focuses in order to perform timely treatment modifications. First, in study I, we involved 52 patients with chronic-phase (CP) CML who used first-line TKIs (imatinib, nilotinib, and dasatinib) for treatment. We used the fold change (FC) in BCR-ABL1 levels between diagnosis (dg) and 1 month as an indicator for early response to treatment. After 1 month of TKI therapy, we identified a poor responders patient group with an inferior long term response. Poor responders did not show any decline in BCR-ABL1 levels during the first month of therapy. Biologically, they were a distinct subgroup with enlarged spleens and a higher Ph+CD34+CD38- stem cell burden at dg. Secondly, in study II, we studied the bone marrow (BM) lymphocytosis phenomenon occurring during TKI therapy. We involved 105 CP CML patients on first-line TKIs (imatinib, dasatinib, and nilotinib) to assess BM lymphocytes by morphology through counting from slides stained by the May-Grünwald-Giemsa (MGG) method and immunophenotyping by flow cytometry. Our results demonstrated that all current TKIs used as first-line treatment in CML induced BM lymphocytosis, which was associated with a better treatment response, as a higher proportion of patients with increased BM lymphocyte counts achieved a 3-month molecular response of BCR-ABL1 transcript levels being less than 10%. However, lymphocytosis occurred in peripheral blood (PB) only during dasatinib therapy. Study III examined hypogammaglobulinemia and the effects of TKI therapy (imatinib, dasatinib, nilotinib, and bosutinib) on B cells. We collected BM and PB samples from 56 first–line TKI treated CP CML patient and found that imatinib treatment decreased IgA and IgG levels, while dasatinib patients had decreased IgM levels. Importantly, we found that an initial decrease in Ig levels at dg predisposed the patient to hypogammaglobulinemia during TKI therapy. Hypogammaglobulinemia was associated only with mild infections, and no severe infections were reported. In conclusion, this thesis demonstrates that after 1 month of TKI therapy, it is already possible to identify the patients who will have inferior long-term responses. Furthermore, TKI treatment induces immunological effects, such as BM lymphocytosis, which are related to therapy responses. In addition to effects on T cells, the B cell compartment is also affected, which can be observed as hypogammaglobulinemia during the treatment. As CML patients are using TKI therapy for years or even decades, immunological monitoring during the course of therapy is warranted.Krooninen myelooinen leukemia (KML) on pahanlaatuinen verisyöpä, joka johtuu kahden kromosomin (9 ja 22) vääränlaisesta yhdistymisestä eli translokaatiosta, mikä johtaa epätavalliseen kromosomimuodostumaan nimeltä Philadelphia-kromosomi. Tämän seurauksena syntyy uusi yhdistelmägeeni, BCR-ABL1-geeni, jota ei normaalisti ole terveillä. Yhdistelmägeeni tuottaa aktiivista tyrosiinikinaasientsyymiä, mikä aiheuttaa erityisesti myelooisten valkosolujen lisääntymistä. KML:ssa on kolme vaihetta. Ensimmäinen vaihe on krooninen vakaa vaihe, ja mikäli tautia ei hoideta, tämän jälkeen seuraavat sairauden vakavammat vaiheet, ns. kiihtynyt vaihe ja blastikriisi, mikä vastaa jo akuuttia leukemiaa. Tällä hetkellä KML:n hoito perustuu BCR-ABL1-tyrosiinikinaasin estoon lääkkeillä, joita kutsutaan tyrosiinikinaasiestäjiksi (TKE-lääkkeet). TKE-lääkkeet estävät poikkeavan tyrosiinikinaasientsyymin toimintaa, minkä seurauksena leukemiasolut kuolevat. Lääkkeen vaikutusta seurataan verinäytteestä määritettävällä BCR-ABL1-geenin määrällä ja kun sen taso on alle 0,1%, katsotaan, että on saavutettu toivottava vaste lääkehoidolle. Tällöin sairaus ei yleensä etene ja potilaat elävät normaalia elämää. Tässä väitöstutkimuksessa tutkittiin TKE-lääkehoidon varhaisia vaikutuksia sekä BCR-ABL1-geenitasoihin että toissijaisia vaikutuksia elimistön immuuni puolustusjärjestelmään. Tavoitteena oli tunnistaa potilaat, joilla on poikkeavan hyvä tai huono vaste TKE-hoitoon, ja analysoida, miten immuunijärjestelmän muutokset vaikuttavat kokonaisvaltaiseen hoitotulokseen. Tämä opinnäytetyö osoitti, että jo yhden kuukauden TKE-hoidon jälkeen on mahdollista tunnistaa joukko potilaita, jotka eivät pidemmällä aikavälillä saavuta toivottavaa hoitovastetta. Lisäksi tutkimuksissa havaittiin, että TKE-hoito aiheuttaa muutoksia elimistön puolustusjärjestelmään. Esimerkiksi osalla potilaista havaittiin lymfosyyttisolujen lisääntymistä luuytimessä, ja tämä oli yhteydessä lääkkeen hoitovasteisiin. Erityisesti toisen polven TKE-lääkkeen dasatinibin osoitettiin vaikuttavan T-lymfosyytteihin lisäämällä niiden sytotoksisia ja syöpäsoluja tuhoavia ominaisuuksia. Lisäksi merkittävällä määrällä potilaista todettiin alentuneita vasta-ainepitoisuuksia TKE-hoidon aikana. Näin ollen immunologinen seuranta hoidon aikana on perusteltua, koska KML-potilaat käyttävät TKE-hoitoa vuosia tai jopa vuosikymmeniä

Polyphenols are potential nutritional adjuvants for targeting COVID-19

© 2020 John Wiley & Sons, Ltd. The newly emerging severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2) is a dangerous pathogen that causes global health problems. It causes a disease called coronavirus disease 2019 (COVID-19) with high morbidity and mortality rates. In SARS-Cov-2-infected patients, elevated oxidative stress and upsurge of inflammatory cytokines are the main pathophysiological events that contribute to the severity and progression of symptoms and death. The polyphenols are natural compounds abundant in fruits and vegetables that are characterized by their high antioxidant and anti-inflammatory effects. Polyphenols have potential as an intervention for preventing respiratory virus infection. The beneficial effects of polyphenols on COVID-19 might be due to multiple mechanisms. Polyphenols can strengthen the body\u27s anti-inflammatory and antioxidant defenses against viral infection. Targeting virus proteins and/or blocking cellular receptors are other plausible antiviral approaches to prevent the entry of the virus and its replication in the host cells. The results on the antiviral effects of various polyphenols, especially on SARS-CoV-2, are promising. The aim of this review is to clarify the role of polyphenols in strengthening antioxidant defenses and upregulating the immune systems of COVID-19 patients and to prevent replication and spreading of the virus

Assessment of bone marrow lymphocytic status during tyrosine kinase inhibitor therapy and its relation to therapy response in chronic myeloid leukaemia

Tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukaemia have been reported to induce immunomodulatory effects. We aimed to assess peripheral blood (PB) and bone marrow (BM) lymphocyte status at the diagnosis and during different TKI therapies and correlate it with treatment responses. BM and PB samples were acquired from 105 first-line TKI-treated patients. Relative number of BM lymphocytes was evaluated from MGG-stained BM aspirates, and immunophenotypic analyses were performed with multicolour flow cytometry. Early 3-month expansion of BM lymphocytes was found during all different TKIs (imatinib n = 71, 20 %; dasatinib n = 25, 21 %; nilotinib n = 9, 22 %; healthy controls n = 14, 12 %, p 10 % (23 vs. 17 %, p <0.05). Detailed phenotypic analysis showed that BM lymphocyte expansion consisted of various lymphocyte subclasses, but especially the proportion of CD19+ B cells and CD3negCD16/56+ NK cells increased from diagnostic values. During dasatinib treatment, the lymphocyte balance in both BM and PB was shifted more to cytotoxic direction (increased CD8+CD57+ and CD8+HLA-DR+ cells, and low T regulatory cells), whereas no major immunophenotypic differences were observed between imatinib and nilotinib patients. Early BM lymphocytosis occurs with all current first-line TKIs and is associated with better treatment responses. PB and BM immunoprofile during dasatinib treatment markedly differs from both imatinib- and nilotinib-treated patients.Peer reviewe