Nader Al-Dewik

Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations

Myeloproliferative neoplasms are clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis. Few therapeutic options are available, among which interferon α (IFNα) presents interesting properties like the ability to induce hematologic responses (HRs) and molecular responses (MRs) in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). HR was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and 2 patients even achieved complete MR. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next-generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2, and TP53 genes). The presence of additional mutations was associated with poorer MR on CALR mutant clones, with only minor or no MRs in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient, but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of HRs and MRs in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy.

Cytomegalovirus-induced Hemorrhagic Colitis in a Patient with Chronic Myeloid Leukemia (Chronic Phase) on Dasatinib as an Upfront Therapy

Dasatinib is a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phase and accelerated (myeloid or lymphoid blast) phase, and CML with resistance or intolerance to prior therapy including imatinib and in adults with Ph+ acute lymphoblastic leukemia 1 The most common adverse reactions (≥15%) in patients with newly diagnosed chronic-phase (CP) CML include myelosuppression, fluid retention, and diarrhea, whereas in patients with resistance or intolerance to prior imatinib therapy, side effects include myelosuppression, fluid retention, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. We report a 39-year-old Ethiopian female patient who received dasatinib as upfront therapy for the treatment of CP-CML who experienced chronic diarrhea for two months, which progressed to hemorrhagic colitis due to cytomegalovirus (CMV) infection of the colon. To our knowledge, this is the first case of CMV colitis in a patient receiving dasatinib as upfront therapy.

A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients

BackgroundProtein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the protein tyrosine phosphatase family known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation including mutations and methylation of CpG islands in the promoter region. Although a critical role in human hematopoiesis and an oncosuppressor role in chronic myeloid leukemia (CML) have been reported, only one polyclonal antibody (named chPTPRG) has been described as capable of recognizing the native antigen of this phosphatase by flow cytometry. Protein biomarkers of CML have not yet found applications in the clinic, and in this study, we have analyzed a group of newly diagnosed CML patients before and after treatment. The aim of this work was to characterize and exploit a newly developed murine monoclonal antibody specific for the PTPRG extracellular domain (named TPγ B9-2) to better define PTPRG protein downregulation in CML patients.MethodsTPγ B9-2 specifically recognizes PTPRG (both human and murine) by flow cytometry, western blotting, immunoprecipitation, and immunohistochemistry.ResultsCo-localization experiments performed with both anti-PTPRG antibodies identified the presence of isoforms and confirmed protein downregulation at diagnosis in the Philadelphia-positive myeloid lineage (including CD34+/CD38bright/dim cells). After effective tyrosine kinase inhibitor (TKI) treatment, its expression recovered in tandem with the return of Philadelphia-negative hematopoiesis. Of note, PTPRG mRNA levels remain unchanged in tyrosine kinase inhibitors (TKI) non-responder patients, confirming that downregulation selectively occurs in primary CML cells.ConclusionsThe availability of this unique antibody permits its evaluation for clinical application including the support for diagnosis and follow-up of these disorders. Evaluation of PTPRG as a potential therapeutic target is also facilitated by the availability of a specific reagent capable to specifically detect its target in various experimental conditions.

Is Adherence to Imatinib Mesylate Treatment Among Patients with Chronic Myeloid Leukemia Associated with Better Clinical Outcomes in Qatar

Background Despite the revolutionary success of introducing tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), for treating chronic myeloid leukemia (CML), a substantial proportion of patients’ treatments fail. Aim This study investigates the correlation between patient adherence and failure of TKIs’ treatment in a follow-up study. Methods This is a follow-up study of a new cohort of CML patients. Adherence to IM is assessed using the Medication Event Monitoring System (MEMS 6 TrackCap, AARDEX Ltd). The 9-item Morisky Medication Adherence Scale, medication possession ratio (MPR) calculation, and the electronic medical records are used for identifying potential factors that influence adherence. Clinical outcomes are assessed according to the European LeukemiaNet 2013 guidelines via reverse transcriptase quantitative polymerase chain reaction measurement of the level of BCR-ABL1 transcripts in peripheral blood. Response is classified at the hematological, cytogenetic, and molecular levels into optimal, suboptimal, or failure. Results A total of 36 CML patients (5 citizens and 31 noncitizen residents) consented to participate in the study. The overall mean MEMS score was 89. Of the 36 patients, 22 (61%) were classified as adherent (mean: 95) and 14 (39%) were classified as nonadherent (mean: 80.2). Adherent patients were significantly more likely to obtain optimal response (95%) compared to the nonadherent group (14.3%; P < 0.0001). The rate of poor adherence was as high as 39% using MEMS, which correlates with 37% treatment failure rate. The survey results show that 97% of patients increased the IM dose by themselves when they felt unwell and 31% of them took the missing IM dose when they remembered. Other factors known to influence adherence show that half of patients developed one or more side effects, 65% of patients experienced lack of funds, 13% of patients declared unavailability of the drug in the NCCCR pharmacy, and 72% of patients believed that IM would cure the disease. The MPR results reveal that 16% of patients had poor access to treatment through the hospital pharmacy. Discussion and Conclusion This is the first prospective study to evaluate CML patients’ adherence and response to IM in Qatar. The high rate of treatment failure observed in Qatar is explained by poor adherence. An economic factor (unaffordable drug prices) is one of the main causes of nonadherence and efforts should be made locally to improve access to medication for cancer diseases. Other risk factors associated with poor adherence could be improved by close monitoring and dose adjustment. Monitoring risk factors for poor adherence and patient education that include direct communication between the health-care teams, doctors, nurses, pharmacists, and patients are essential components for maximizing the benefits of TKI therapy and could rectify this problem. The preliminary results show that patients’ response to treatment may be directly linked to patients’ adherence to treatment. However, further in-depth and specific analysis may be necessary in a larger cohort.

A Case of Chronic Neutrophilic Leukemia Successfully Treated with Pegylated Interferon Alpha-2a

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that represents a diagnostic dilemma for both clinicians and pathologists. Because this disease entity is very rare, and because its diagnosis is by exclusion, it is important for clinical hematologists and hemato-pathologists to be familiar with CNL when approaching patients with MPNs and persistent neutrophilia. A woman in her 40s who was incidentally found to have leukocytosis was referred to the hematology service at the National Center for Cancer Care and Research for evaluation. Complete blood count revealed hyperleukocytosis with predominant neutrophilia. Peripheral blood and flow cytometry did not show any evidence of lymphoproliferative disorder or myeloblasts. Bone marrow aspirate and biopsy revealed a hypercellular marrow with myeloid hyperplasia. Cytogenetics revealed normal karyotype. Tests for both Janus kinase mutation JAK2 V617F and rearrangement of the genes BCR–ABL1, platelet-derived growth factor receptor-α (PDGFRα), PDGFRβ, and fibroblast growth factor receptor-1 (FGFR1) were negative. Thereafter, the diagnosis of CNL was reached. She was treated with pegylated interferon alpha-2a, with very good hematological response. To the best of our knowledge, this is the first case of CNL reported among the Arab population.

Dasatinib Induced Avascular Necrosis of Femoral Head in Adult Patient with Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia (Ph) chromosome resulting from the reciprocal translocation t(9;22)(q34;q11). The molecular consequence of this translocation is the generation of the BCR-ABL fusion gene, which encodes a constitutively active protein tyrosine kinase. The oncogenic protein tyrosine kinase, which is located in the cytoplasm, is responsible for the leukemia phenotype through the constitutive activation of multiple signaling pathways involved in the cell cycle and in adhesion and apoptosis. Avascular necrosis of the femoral head (AVNFH) is not a specific disease. It occurs as a complication or secondary to various causes. These conditions probably lead to impaired blood supply to the femoral head. The diagnosis of AVNFH is based on clinical findings and is supported by specific radiological manifestations. We reported a case of a 34-year-old Sudanese female with CML who developed AVNFH after receiving dasatinib as a second-line therapy. Though the mechanism by which dasatinib can cause avascular necrosis (AVN) is not clear, it can be postulated because of microcirculatory obstruction of the femoral head. To the best of our knowledge and after extensive literature search, this is the first reported case of AVNFH induced by dasatinib in a patient with CML.

Clinical genetics and genomic medicine in Qatar

Clinical genetics and genomic medicine in Qatar.

Studying the Impact of Presence of Alpha Acid Glycoprotein and Protein Glycoprotein in Chronic Myeloid Leukemia Patients Treated with Imatinib Mesylate in the State of Qatar

Despite the efficacy of imatinib mesylate (IM) in treating chronic myeloid leukemia (CML), there is a high degree of resistance. Alpha-1-acid glycoprotein may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target, while protein glycoprotein (PGP) may reduce the intracellular concentration of the drug via an active pump mechanism. We thus investigated the correlation between AGP and PGP levels and the resistance/response to treatment. A total of 26 CML patients were investigated for AGP and PGP levels at diagnosis and during treatment. There was no significant difference or correlation between AGP levels and the different groups of patients. There was also no significant difference in the fluorescence intensities of PGP levels among the different patient groups. The resistance observed in our CML patient population could not be correlated with AGP and PGP levels. There was no significant pattern of AGP and PGP expression, irrespective of the response or resistance to treatment.

BCR-ABL Kinase Point Mutations don't Correlate with the Resistance of Chronic Myelocytic Leukemia (CML) to Imatinib Mesylate (IM); A Study on CML Patient Population in Qatar

Abstract Background: More than 45% of CML patients in Qatar resist the first line of treatment; Internationally, certain ABL mutations are the most common cause of IM resistance Objectives: To screen for BCR-ABL kinase mutations in CML patients treated in Qatar and to study if point mutations can be correlated with resistance to treatment. Methods: Peripheral Blood (PB) and Bone Marrow (BM) samples were collected from 25 patients; total RNA was extracted and cDNA was produced via RT-PCR with special precautions to avoid amplification of wild type ABL and cover the whole ABL kinase domain. Results: Over a period of three years, 39 PB and 30 BM samples from 25 patients receiving IM were studied for ABL mutations prior to treatment and at time of resistance. For all 25 patients we noticed three nucleotide changes at A1258G, A1426G and A1739G of ABL (GenBank accession no. M14752). However, when we compared these changes with major SNP databases (NCBI, ENSEMBL), these changes were described by others as ancest...