Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms.

The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and diffuse large B cell lymphoma. Covalent BTKi (namely ibrutinib, acalabrutinib, and zanubrutinib) functions by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. Despite the high efficacy and safety of BTKi treatment, a significant fraction of patients affected by B cell malignancies who are treated with these drugs experience disease relapse. Several mechanisms of resistance to covalent BTKi, including Cys-481 mutations of BTK, have been investigated in B cell malignancies. Non-covalent BTKi, such as pirtobrutinib, have been developed and proven effective in patients carrying both Cys-481-mutated and unmutated BTK. Moreover, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms.

Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Despite its indolent clinical course, therapy refractoriness and disease progression still represent an unmet clinical need. Before the advent of pathway inhibitors, chemoimmunotherapy (CIT) was the commonest option for CLL treatment and is still widely used in areas with limited access to pathway inhibitors. Several biomarkers of refractoriness to CIT have been highlighted, including the unmutated status of immunoglobulin heavy chain variable genes and genetic lesions of TP53, BIRC3 and NOTCH1. In order to overcome resistance to CIT, targeted pathway inhibitors have become the standard of care for the treatment of CLL, with practice-changing results obtained through the inhibitors of Bruton tyrosine kinase (BTK) and BCL2. However, several acquired genetic lesions causing resistance to covalent and noncovalent BTK inhibitors have been reported, including point mutations of both BTK (e.g., C481S and L528W) and PLCG2 (e.g., R665W). Multiple mechanisms are involved in resistance to the BCL2 inhibitor venetoclax, including point mutations that impair drug binding, the upregulation of BCL2-related anti-apoptotic family members, and microenvironmental alterations. Recently, immune checkpoint inhibitors and CAR-T cells have been tested for CLL treatment, obtaining conflicting results. Potential refractoriness biomarkers to immunotherapy were identified, including abnormal levels of circulating IL-10 and IL-6 and the reduced presence of CD27+CD45RO- CD8+ T cells.

In vitro study of the effect of resveratrol purified from the skin of Iraqi black grape (Vitis vinifera) on lymphocyte cultures isolated from the blood of patients with lymphoma.

The natural stilbene compound resveratrol (RSV) was extracted and purified locally from the black grape skin (Vitis vinifera) cultivated in Iraq. Cultures of human peripheral lymphocytes were obtained from the blood samples of patients with and without lymphoma to be treated with RSV at different concentrations. Three RSV concentration levels were subjected to isolated lymphocytes from blood samples of Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and without lymphoma to estimate the change in TNF-α and IL-10. Resveratrol seemed to differently affect cytokines level in normal and lymphoma lymphocytes in relation to its concentration. The lowest resveratrol concentration (50 µg/ml) decreased TNF-α levels for patients without lymphoma and all NHL patients in contrast to the HL sample. Treating normal lymphocytes with a higher dose (1000 µg/ml) might elevate the levels of TNF-α in almost all samples. There was an inverse relationship between both cytokines in most treatments; with the increase in TNF-α level, there was a decrease in IL-10 level except in HL and normal lymphocytes treatment. The locally purified resveratrol could serve as a multi-target drug that modulates the immune system to improve body defense in patients suffering from lymphoma and in patients without lymphoma by altering cytokine levels in response to different resveratrol concentrations in a different manner.

Efficacy and safety of biosimilar rituximab (ZytuxTM) in newly diagnosed patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL) are considered parts of mature B cell neoplasms in WHO classification. They are both characterized by accumulation of B cells in blood, lymphoid tissues and bone marrow. Most of treatment protocols of NHL and CLL contain rituximab in addition to chemotherapy, which has been associated with improved survival. The aim of this study was to assess the efficacy and safety of Zytux™ (AryoGen Pharmed) in newly diagnosed patients with NHL and CLL. A prospective single center study conducted at the National Center of Hematology, Mustansiriyah University, from January 2018 till October 2018. Twenty patients were included in this study, ten of them were NHL and ten patients were CLL. All patients were treated with Zytux™ in addition to designated protocol. All patient were followed up for 6 months and evaluated at the end of each protocol. There were 20 patients in this study; the overall median age for all patients in this study was 66 years. The median age was 57.5 years for NHL and 68.5 years for CLL. There were 13 males and 7 females in total, with male predominance in both groups. Regarding safety profile, Zytux™ demonstrated similar adverse reactions in comparison to MabThera® (Roche Spa). Moreover, the overall response rate in both groups was 85% with complete response achieved in 35% and partial response in remaining 50%.This study concluded that the early results of use of Zytux™ in NHL and CLL were not inferior to reference drug MabThera® in contrast it was comparable and even better in term of safety and efficacy.

Effects of nilotinib on platelet function in patients with chronic myeloid leukemia in chronic phase.

BACKGROUND: Tyrosine kinases are highly expressed in platelets and play an important role in their activation process. Some studies have reported the blocking effects of tyrosine kinase inhibitors on different platelet functions. OBJECTIVES: Evaluate the effects of nilotinib on platelets aggregation in 42 patients with chronic phase of CML and correlate the results with clinical and hematological parameters: age, complete blood count and presentation. PATIENTS AND METHODS: This study was conducted on 42 patients diagnosed as Chronic Phase of Chronic Myeloid Leukemia based on clinical, morphological and cytogenetic study. All patients were on Nilotinib treatment and were attending the National Center of Hematology in Baghdad. About 9 mL of venous blood sample were collected from each patient and control subjects, samples divided into 3 parts for complete blood count, platelet aggregation test and PT and aPTT. RESULTS: The mean age was 41.3 ±â€¯1.7 (mean ±â€¯SEM) years old. M:F ratio of 1.2:1. Mean duration of nilotinib therapy(1.4 years). All patients had normal PT and aPTT.Only 16 (38%) patients had abnormal aggregation response to epinephrine, but there was no statistically significant differences with control group. CONCLUSION: Nilotinib had no adverse effect on platelet function nor patients clotting tests.

The Efficacy of Fludarabine, High Dose Cytosine Arabinoside with Granulocyte Colony Stimulating Factor (FLAG) Protocol as Salvage Therapy for Refractory/Relapsed Acute Leukemias in Adult Iraqi Patients.

Refractory/relapsed acute leukemia has always been a challenging problem for hematologist. Over the past decade emphasis has been made in the development of regimens containing fludarabine, combined with cytosine arabinoside for the treatment of refractory/relapsed acute leukemias. The aim of this study is to evaluate the efficacy and toxicity of the combination of fludarabine, high dose cytarabine, and granulocyte colony stimulating factor in refractory relapsed cases of acute leukaemia, a prospective study is being conducted at the National Center of Hematology and hematology unit/Baghdad teaching hospital from July 2008 to July 2010. Twenty Patients with refractory/relapsed acute leukemia were treated with fludarabine 30 mg/m(2) and cytosine arabinoside (Ara-C) 2 g/m(2) for 5 days, and granulocyte colony stimulating factor G-CSF 300 µg/day from day 0 till neutrophil recovery (ANC > 1.0 × 10(9)/L). Response was evaluated by bone marrow examination on day 30 post chemotherapy. Patients included were refractory acute lymphoblastic leukemia (ALL) (five patients), relapsed ALL (four patients), refractory acute myeloid leukemia (AML) (eight patients), relapsed AML (three patients). Complete remission (CR) was achieved in nine (45 %) patients, while three (15 %) patients got partial remission. Three (15 %) patients died because of post chemotherapy complications and five (25 %) patient failed to achieve remission. Major complications encountered were: anemia, fever, bleeding, mucositis and bacterial infections. FLAG protocol is well tolerated and effective regimen in relapsed/refractory acute leukemias. The toxicity is acceptable, enabling most patients to receive further treatment, including transplantation procedures.

Prospective single-center study of chronic myeloid leukemia in chronic phase: switching from branded imatinib to a copy drug and back.

Imatinib (Glivec(®)/Gleevec(®)) has shown long-term efficacy and safety in randomized trials. No large-scale studies have prospectively assessed the benefit-risk profile of an imatinib copy drug. We prospectively evaluated the response of patients with chronic myeloid leukemia in chronic phase in one institution. Patients with a complete hematologic response (n = 126) switched from branded imatinib to an imatinib copy drug. Subsequently, all patients switched back to the branded imatinib. Many patients in this study had a loss of hematologic response and tolerability issues with the imatinib copy drug. Hematologic response and tolerability improved upon retreatment with branded Glivec.

Evaluation of the safety of imatinib mesylate in 200 iraqi patients with chronic myeloid leukemia in the chronic phase: single-center study.

OBJECTIVE: Imatinib mesylate, a tyrosine kinase inhibitor, is presently the drug of choice for chronic myeloid leukemia (CML). During therapy, a few patients may develop hematological and non-hematological adverse effects. MATERIALS AND METHODS: The aim of this study was to evaluate the safety of imatinib therapy in patients with CML. Between December 2007 and October 2009 two hundred patients with CML in chronic phase were included in the study. Written informed consent was obtained from all patients prior to the start of the study. Imatinib was started at 400 mg orally daily. Patients were monitored carefully for any adverse effects. Complete blood count, liver, and renal function tests were done once in 2 weeks during the first month and on a monthly basis during follow-up. Toxicities that encountered were graded as per the National Cancer Institute common toxicity criteria version 2. Both hematologic and non-hematologic toxicities were managed with short interruptions of treatment and supportive measures, but the daily dose of imatinib was not reduced below 300 mg/day. RESULTS: Two hundred CML patients in chronic phase were included in this study; the male:female ratio was 0.7:1 with mean age 39.06±13.21 years (ranged from 15-81 years). The study showed that the commonest hematological side effects were grade 2 anemia (12.5%) followed by leukopenia (8%) and thrombocytopenia (4%), while the most common non-hematological adverse effects were superficial edema and weight gain (51.5%), followed by musculoskeletal pain (35.5%), then gastro-intestinal symptoms (vomiting, diarrhea) (19%). Fluid retention was the commonest side effect, which responded to low-dose diuretics. The drug was safe and well tolerated. There were no deaths due to toxicity. CONCLUSION: Imatinib mesylate a well-tolerated drug, and all undesirable effects could be ameliorated easily. The most common hematological and non-hematological side effects were anemia and fluid retention, respectively Conflict of interest:None declared.