Clinical Outcomes of Patients with Chronic Myeloid Leukemia and COVID-19 Infection-A Single Center Survey.

Background: Previous research has shown different effects of hematological malignancies on the outcome of patients with COVID-19 infection depending on the type of disease and the treatment received. This research was aimed at examining the clinical outcome of COVID-19 infection in positive patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Methods: We collected retrospective information on chronic myeloid leukemia patients who were treated and monitored in our institution during the pandemic period. Within this cohort, we recorded COVID-19 positive symptomatic patients and analyzed their basic characteristics, symptoms, severity, and outcome. Results: In the study cohort when COVID-19 was diagnosed, 86.7% of patients were on first-generation tyrosine kinase inhibitors therapy-imatinib. At the time of infection, 70% of patients were in molecular remission, 23.4% in complete cytogenetic remission, and 3.3% in complete hematological response. Most patients had symptomatic disease. Within the analyzed group, 56.7% of patients had asymptomatic/mild COVID-19 infection, 23.3% of patients had moderate symptoms which did not require hospitalization, and 20% of patients had severe/critical symptoms that required admission to the intensive care unit. More than half of the patients interrupted treatment with tyrosine kinase inhibitors temporarily during COVID-19. There were no deaths due to COVID-19 infection. Conclusions: In compliance with other larger clinical studies, analysis of the clinical outcome of COVID-19 infection in patients with chronic myeloid leukemia on tyrosine kinase inhibitors therapy in this study showed that they do not have an increased risk for COVID-19 infection and that they have a mild course of the disease with recovery.

The effect of curcumin and PI3K/Akt inhibitor on monosodium glutamate-induced rat thymocytes toxicity.

Monosodium glutamate (MSG), the sodium salt of glutamic acid, is widely used in modern nutrition as flavor enhancer. However, it has been shown that curcumin has ability to induce apoptosis in the cells of the immune system. In the present study, we evaluate the potential protective effects of curcumin in MSG-induced apoptosis and signaling pathway which may be involved. Rat thymocytes were treated with increased (1, 10, 50 mM) MSG concentrations and/or curcumin (3 µM). Cell apoptosis rate, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), Bcl-2, Bax protein expression and caspase-3 activity were determined after 24 hours of incubation. Treatment with MSG resulted with increased apoptosis, ROS production and caspase-3 activity, followed with decreased MMP and Bcl-2/Bax protein ratio. Inhibition of caspase-3 and caspase-9 activity reduced cell apoptosis, indicating the involvement of mitochondrial apoptotic pathway. Co-treatment with curcumin markedly reduced apoptosis and ROS production, together with increased MMP and Bcl2/Bax protein ratio. Inhibition of PI3K/Akt signaling pathway abolished protective effect of curcumin in MSG-induced toxicity in rat thymocytes. Obtained findings suggest that curcumin may attenuate the MSG-induced apoptosis through PI3K/Akt signaling pathway which could be useful in preventing the potential deficiencies in T cell-mediated immunity.

The significance of angiogenesis for predicting optimal therapeutic response in chronic myeloid leukaemia patients.

In this study the correlation and the prognostic value of the morphometric parameters of angiogenesis for optimal therapeutic response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukaemia (CML), i.e. complete cytogenetic response (CCgR) and major molecular response (MMoR), were investigated. Microvascular density (MVD) and a number of different size- and shape-related morphometric parameters of microvessels of bone marrow biopsy from 40 CML patients and 20 controls were examined. Microvessels of bone marrow were examined by using immunohistochemical staining for CD34 and quantified in the region of the most intense vascularisation by using image analysis. CML patients had significantly higher angiogenesis parameters when compared with controls. A statistically significant correlation was found between some parameters of angiogenesis and evaluated CCgR and MMoR. For achievement of CCgR, lower values of MVD, minor axis, area, circularity, and roundness and higher value of aspect ratio, while for achievement of MMoR only lower values of MVD have been identified as positive prognostic factors. Besides confirming increased angiogenesis in CML patients, this study also demonstrated prognostic significance of the degree of angiogenesis for the clinical outcome and identified angiogenic predictive factors for achieving optimal response on TKIs therapy.

Impact of quality of response on survival outcomes among multiple myeloma patients treated with novel agents - a retrospective analysis.

BACKGROUND: In this era of target therapies, novel data on the correlation between response endpoints and survival outcomes in multiple myeloma have arisen. OBJECTIVE: To determine the impact of quality of response on clinical outcomes, using first-line treatment, and identify risk factors influencing progression-free survival (PFS) and overall survival (OS) among myeloma patients. DESIGN AND SETTING: Retrospective analysis on myeloma patients who were treated at the Clinic of Hematology and Clinical Immunology, University Clinical Centre, Nis, Serbia, over a four-year period. METHODS: A total of 108 newly diagnosed patients who received first-line therapy consisting of conventional chemotherapy or novel agent-based regimens were included in this analysis. RESULTS: The quality of response to first-line therapy for the whole cohort was classified as follows: complete response (CR) in 19%; very good partial response (VGPR) in 23%; partial response (PR) in 38%; and less than PR for the remaining patients. After a median follow-up of 25.4 months, the three-year PFS and OS for the entire study population were 47% and 70%, respectively. Achievement of CR was the main factor associated with significantly prolonged PFS and OS, in comparison with patients who reached VGPR and PR. Likewise, addition of the new drugs bortezomib and thalidomide to standard chemotherapy led to considerably extended PFS and OS, compared with conventional therapy alone. CONCLUSIONS: This analysis demonstrated that the quality of response after application of first-line treatment using novel agent-based regimens among multiple myeloma patients was a prognostic factor for PFS and OS, which are the most clinically relevant outcomes.

Generic Imatinib in Chronic Myeloid Leukemia Treatment: Long-Term Follow-up.

BACKGROUND: Similar to the application of other generic drugs, the use of generic imatinib in the treatment of chronic myeloid leukemia (CML) leads to significant cost savings, but it also raises issues related to efficacy, safety, and quality. This study assessed the long-term outcome of CML patients after administration of generic imatinib. PATIENTS AND METHODS: The cohort of 83 patients was divided into 2 groups depending on whether generic imatinib was applied in the front-line setting or after switching from original imatinib. The groups were compared regarding rates of optimal treatment response, adverse events, and survival. RESULTS: In the first group, at the time of switching, rates of complete cytogenetic response experienced, and major molecular response were 95% and 87.5% of patients in the front-line generic imatinib group and the group that switched from original to generic imatinib, respectively. After 24 months of treatment with generic imatinib, the rates of sustained, lost, and experienced major molecular response were 72.5%, 15%, and 12.5%, respectively. In the group treated with front-line generic imatinib at 6 months, 67.4% experienced complete cytogenetic response, while for major molecular response at 12 and 24 months, it was 58.1% and 69.8%, respectively. Estimated 5-year overall survival in the group treated with front-line generic imatinib was 86.1%, while 10-year overall survival in the group treated with second-line generic imatinib was 93.8%. CONCLUSION: Results of this study with long-term follow-up are further evidence that generic imatinib is at least noninferior to original imatinib regarding efficacy and survival, both when provided initially and as a subsequent replacement for original imatinib.

Analyses of Treatment Outcome According to Age in Patients With Chronic Myeloid Leukemia Receiving Front-line Imatinib Therapy.

BACKGROUND: Previous studies have indicated that the effect of age at the diagnosis of chronic myeloid leukemia (CML) is minimized in patients treated with imatinib. The treatment response and survival rates were similar for younger and elderly patients. The aim of the present study was to evaluate the effect of age on the treatment outcomes in patients with CML receiving front-line imatinib therapy. PATIENTS AND METHODS: Using age, 101 patients were divided into 3 groups: young (age, 18-44 years; YP), middle-age (age, 45-64 years; MP), and elderly (age, ≥ 65 years; EP). The patients' clinical features, treatment responses, survival, and adverse events were evaluated. RESULTS: The complete cytogenetic response rates were similar in all 3 groups (81.8% in YP, 86.8% in MP, and 76.7% in EP; P = .328). However, the major molecular response rate was greatest in the MP group (84.2% vs. 63.6% in the YP and 60.0% in the EP group; P < .001). Most of the nonhematologic adverse events (all grades) were in the EP group (40.0% vs. 27.3% in the YP and 21.1% in the MP group; P = .005). The estimated 6-year event-free survival in the MP group (75.5%) was significantly greater than that in the YP group (58.6%) or EP group (43.4%). Also, the estimated 6-year overall survival rate in the EP group (73.5%) was significantly lower than that in the YP group (90.8%) and MP group (86.4%) (P < .001 for all). CONCLUSION: Our results have shown that middle-age patients have the best clinical outcomes, with the greatest rates of an optimal therapeutic response, longer event-free survival, and longer overall survival.

Impact of quality of response on survival outcomes among multiple myeloma patients treated with novel agents - a retrospective analysis

Abstract BACKGROUND: In this era of target therapies, novel data on the correlation between response endpoints and survival outcomes in multiple myeloma have arisen. OBJECTIVE: To determine the impact of quality of response on clinical outcomes, using first-line treatment, and identify risk factors influencing progression-free survival (PFS) and overall survival (OS) among myeloma patients. DESIGN AND SETTING: Retrospective analysis on myeloma patients who were treated at the Clinic of Hematology and Clinical Immunology, University Clinical Centre, Niš, Serbia, over a four-year period. METHODS: A total of 108 newly diagnosed patients who received first-line therapy consisting of conventional chemotherapy or novel agent-based regimens were included in this analysis. RESULTS: The quality of response to first-line therapy for the whole cohort was classified as follows: complete response (CR) in 19%; very good partial response (VGPR) in 23%; partial response (PR) in 38%; and less than PR for the remaining patients. After a median follow-up of 25.4 months, the three-year PFS and OS for the entire study population were 47% and 70%, respectively. Achievement of CR was the main factor associated with significantly prolonged PFS and OS, in comparison with patients who reached VGPR and PR. Likewise, addition of the new drugs bortezomib and thalidomide to standard chemotherapy led to considerably extended PFS and OS, compared with conventional therapy alone. CONCLUSIONS: This analysis demonstrated that the quality of response after application of first-line treatment using novel agent-based regimens among multiple myeloma patients was a prognostic factor for PFS and OS, which are the most clinically relevant outcomes.

Improved prediction of clinical outcome in chronic myeloid leukemia.

We sought to develop and compare prognostic models, based on clinical and/or morphometric diagnostic data, to enable better prediction of complete cytogenetic response (CCgR). This prospective longitudinal study included a consecutive series of patients with chronic myeloid leukemia (CML) who were started on imatinib therapy. Logistic regression analysis using backward selection was performed with CCgR at 6, 12, and 18 months as the outcome variables. We evaluated both calibration and discrimination of the model. Internal validation of the model was performed with bootstrapping techniques. A total of 40 patients on imatinib therapy were included in the final analysis. Of these, 25 (62.5 %), 29 (72.5 %), and 32 (80 %), respectively, achieved CCgR at 6, 12, and 18 months after initiation of imatinib. Models included EUTOS score on diagnosis and one of the following morphometric parameters: microvascular density, length of the minor axis, area or circularity of the blood vessel. Models including morphometric parameters and EUTOS score were superior for prediction of CCgR at 6, 12, and 18 months. In particular, the superior models showed better specificity than EUTOS score alone. Using morphometric parameters in conjunction with EUTOS score improves prediction of CCgR. If validated, these models could aid in individual patient risk stratification.

[Factors associated with achievement and durability of cytogenetic response in patients with chronic myeloid leukemia treated with imatinib].

BACKGROUND/AIM: Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has revolutionized the treatment of Bcr-Abl positive chronic myeloid leukemia and become the standard of care for this disease. The aim of this study was evaluation and analysis of cytogenetic response in different intervals and risk groups as well as finding association between pre-treatment characteristics and later probability of achievement of major cytogenetic response. METHODS: We analyzed a total of 22 adult patients with newly diagnosed Philadelphia positive early chronic phase chronic myeloid leukemia treated at our institution from June 2006 to December 2009. RESULTS: The median follow-up time for patients during treatment with imatinib was 25.7 months (range, 12-42 months). A complete hematologic response was achieved in all of the analyzed patients within 6 months from the start of the treatment. The major cytogenetic response rate was 81.8%, and the complete cytogenetic response rate was 72.7%. The patients with low or moderate relative risk had the rate of complementary achieving major and complete cytogenetic response of 75-90%. A multivariate analysis identified the following independent prognostic factors for achieving major cytogenetic response: the absence of splenomegaly, white blood cell count less than 10 x 10(9)/L, the platelet count less than 450 x 10(9)/L, the presence of less than 5% of bone marrow blasts and basophils, the absence of blasts in peripheral blood, the presence of less than 7% of basophils in peripheral blood. CONCLUSION: Patients who early achieve complete and major cytogenetic response as well as those with low and moderate relative risk have a higher rate of achieving and maintaining complete cytogenetic response. There are also characteristics of patients before treatment that may indicate the treatment outcome.

Prognostic factors associated with complete cytogenetic response in patients with chronic myelogenous leukemia on imatinib mesylate therapy.

INTRODUCTION: Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has proved to be most effective therapy of Philadelphia chromosome-positive chronic myelogenous leukemia. Imatinib induces complete haematological and cytogenetic response in high percentage of patients. OBJECTIVE: The aim of this study was to identify potential prognostic factors before beginning treatment with imatinib associated with complete cytogenetic response. METHODS: We analyzed 20 patients with newly diagnosed Philadelphia positive chronic myelogenous leukemia treated at our institution from June 2006 until May 2009. These patients were treated with imatinib mesylate in oral dose of 400 to 800 mg daily. Complete blood counts were performed every month, while serum chemistry evaluations and bone marrow evaluations including morphology and cytogenetics were performed every 6 months. RESULTS: Of the 20 patients analyzed in this study, 19 (95%) achieved complete haematologic response within three months. In all patients cytogenetic analyses were done and all have achieved absolute cytogenetic response. The best cytogenetic response rate at any time during study treatment among 20 patients was: complete cytogenetic response in 15, partial cytogenetic response in three and minor cytogenetic response in two patients. Among 11 observed base-line patients' characteristics five were independent predictors of a high rate of complete cytogenetic response; the absence of blasts and basophils in peripheral blood, the presence of less than 5 percent of bone marrow blasts, white blood cell count less than 10 x 10(9)/L and the absence of splenomegaly (p < 0.01). CONCLUSION: Our results showed that some pre-treatment characteristics of patients might be the cause of differences in treatment outcome. On the basis of this analysis, we identified several pre-treatment patients' characteristics to be independent prognostic factors for achievement of complete cytogenetic response.

Hematopathologic and cytogenetic findings in imatinib mesylate treated chronic myelogenous leukemia patients: 2.5 years' experience.

BACKGROUND/AIM: Imatinib mesylate, a tyrosine kinase inhibitor with specific activity against the breakpoint cluster region--Abelson murine leukemia (BCR-ABL) tyrosine kinase has been developed for treatment of chronic myelogenous leukemia (CML). Its hematologic and cytogenetic effects have been evaluated in a series of clinical trials. The aim of this study was to report hematologic and cytogenetic response in CML patients during the treatment with imatinib mesylate. METHODS: A total of 21 patients were treated and observed from July 2006 to December 2008. The median time from CML diagnosis was no more than 12 months, so all the patients received previous treatment with hydroxyurea for which the median time was 3 months. The patients received imatinib mesylate in an effective oral dose of 400 to 800 mg daily, which was followed with peripheral blood counts, bone marrow examination, and cytogenetic studies at 6, 12, 18 and 24 months. RESULTS: Complete hematologic responses were reported for 19 (90.48%) of 21 patients studied. Among 19 patients who had a response, 16 (86%) did so within 3 months. The best cytogenetic response rate at any time during the study treatment with imatinib mesylate, among 14 patients in which cytogenetic response evaluated was: complete cytogenetic response in 7 (50%) patients, partial cytogenetic response in 6 (42.9%) patients and minor cytogenetic response in 1 (7.1%) patient. No patients had progressed to accelerated or blastic phase. The most frequent adverse effects that seemed to be related to treatment with imatinib mesylate were edema and musculoskeletal pain; overall, most were mild. Only one patient discontinued treatment because of hematologic toxic effects. CONCLUSION: The results obtained in this study confirm that imatinib mesylate induces a complete hematological and cytogenetic response in a high percentage of patients with chronic-phase CML.

[Successful treatment of acquired haemophila associated with psoriasis--case report].

Acquired factor VIII (FVIII) inhibitor causes a rare but life-threatening form of bleeding disorder, owing to the formation of autoantibodies against FVIII. Treatment modalities include the use of immunosuppressive drugs, such as cyclophosphamide and corticosteroids, plasmapheresis, and i.v. immunoglobulin. The case of a 67-year-old patient with acquired FVIII inhibitor and psoriasis presented us with a serious bleeding complication. Bleeding reacted poorly to therapy with corticosteroids and cyclophosphamide. Treatment with cyclosporin, however, resulted in a prompt and complete response. The lack of side effects and the relatively quick response suggest that cyclosporin A should be tried as a frontline treatment for patients with acquired FVIII inhibitor.