Sociodemographic Characteristics Of Survival In Patients With Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous group of acquired hematopoietic stem cell disоrders characterized by ineffective hematopoiesis and a high risk of transformation into acute myeloid leukemia (AML). Due to the phenotypic diversity of MDS, survival widely varies. The purpose of the present study is to analyze the impact of some socio-demographic characteristics on the survival of patients with MDS. We analyzed 219 patients with MDS, who were admitted in the Clinic of Hematology, University Hospital "St. Marina”- Varna for a period of 10 years (2010-2020). Survival was assessed by age, sex, FAB and WHO2016 subtype and risk group defined by IPSS, IPSS-R and WPSS. There is a significantly higher survival rate in women and an inversely proportional relationship between survival and age. Patients with RAEB and RAEB-t have the lowest survival as well as patients with high and very high risk. MDS presents with significant differences in survival between subtypes, age and sex. The outcome of the disease varies according to the risk group determined by the established scales for risk stratification, and the most accurate in the prognosis is IPSS-R

Outcome after azacitidine treatment in patients with high-risk myelodysplastic syndrome and acute myeloid leukemia in the Clinic of Hematology at St. Marina University Hospital, Varna

Introduction: Hypomethylating agents have become a standard therapy for high-risk myelodysplastic syndromes (MDS) and elderly patients with acute myeloid leukemia (AML).Aim: The aim of the study was to assess the efficacy of azacitidine treatment in patients with MDS and AML followed for 18 months.Materials and Methods: Twenty-seven patients with MDS and AML treated in the Clinic of Hematology at St. Marina University Hospital, Varna were included in the study. Azacitidine was administered subcutaneously in at a dose of 75 mg/m2 for 7 days. Disease assessment was performed on  the 3rd month, 6th month, and at progression.Results: Twenty-seven patients were analyzed. Their median age was 71.5 years. Nine had refractory anemia with excess of blasts II (RAEB II), 5 had chronic myelomonocytic leukemia II (CMML II), 1 was with unclassifiable MDS (MDS-U), and 12 with AML. The median number of administered cycles was 6 (1-19). Eleven patients completed 6 cycles of azacitidine. Partial response was achieved in 9 patients (33%) (7 MDS and 2 AML), stable disease in 8 (29%) (5 MDS and 3 AML). Progressive disease was observed in 10 patients (37%). The response correlated with the type of the disease (p=0.03), cytogenetic risk (p=0.01), and survival (p=0.000). At 18 months, 60% of MDS patients were alive compared to 41.7% in the AML group. The median time to death in the AML patient group was 2.5 months. The mean overall survival was 10.4 months (12.6 months for MDS patients and 5.4 months for AML patients).Conclusion: The therapy with azacitidine is an option for elderly patients with high-risk MDS.  In patients with AML a rapid progression is observed during the first two cycles with mortality rate of 58.3%

Long-term treatment with rilzabrutinib in patients with immune thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibodymediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of =50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts =30 × 109/L and =50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals.</p

The role of MDS-CI in the prognostic assessment of patients with myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous group of acquired hematopoietic stem cell disorders characterized by ineffective hematopoiesis and a high risk of transformation into acute myeloid leukemia (AML). The MDS comorbidity index (MDS-CI) is designed to predict the impact of comorbidities on the outcome of the disease. Тhe aim of our analysis is to assess the prognostic value of MDS-CI within the WHO prognostic scoring system (WPSS) subgroups. We applied MDS-CI in 219 patients with MDS, diagnosed and treated in the Clinic of Hematology of St. Marina University Hospital, Varna, Bulgaria between May 2010 and May 2020. WPSS was used for prognostic stratification. Statistical analysis was performed using SPSS 20. We found that the mean age of patients with MDS was 70.7 ± 10.2 years (35–93 years). In patients with very low/low risk according to WPSS, we found significant difference in terms of survival between MDS-CI = 0 and MDS-CI > 2 (69.2 ± 43.0 vs. 38.3 ± 42.1 months, p < 0.001). Similar difference was found within the intermediate/very high risk groups (p < 0.001). MDS-CI adds prognostic value to the established WPSS. Combining both systems allows refining the prognostic assessment and survival of MDS patients

Clinical, Biological and Genetic Markers in Risk Stratification in Patients with Myelodysplastic Syndrome // Клинико-биологични и генетични маркери в рисковата стратификация при пациенти с миелодиспластичен синдром

Myelodysplastic syndrome (MDS) is a heterogeneous group of hematopoietic stem cell disorders characterized by ineffective hematopoiesis, cytopenia, and an increased risk of transformation into acute myeloid leukaemia (AML). The risk stratification is carried out through the approved scales of the International Prognostic Scoring System (IPSS), its revised version (IPSS-R) and the World Health Organization-based scoring system (WPSS). Established risk scales do not include prognostic factors related to the patient, such as general health, comorbidities, and degree of manifestation. Comorbidities and the degree of "frailty" play a role in determining the survival of patients with MDS. The addition of comorbid indices as an additional factor to the established risk scales significantly improves the prognosis. We established the role of clinical and biological factors. Significant prognostic factors for the course of the disease are the percentage of myeloblasts in CM, haemoglobin levels, MCV platelet and leukocyte count, serum iron, LDH, cytogenetic disorders and the number and degree of dysplasia. We have shown that patients with severe comorbidities have a 50% reduced survival, regardless of age and risk group. Determining risk using the risk stratification and comorbidity scales using comorbid indices significantly improves prognostic assessment in patients with MDS. Combining them allows for more precise risk stratification and forecasting.MДС е хетерогенна група от клонални заболявания на хематопоетичната стволова клетка, характеризиращи се с неефективна хемопоеза, периферна цитопения и повишен риск от трансформация в ОМЛ. Рисковата стратификация се осъществява чрез утвърдените скали на международната прогностична скоринг система (IPSS), ревизираната й версия (IPSS-R) и базираната на Световната здравна организация скоринг система (WPSS). Утвърдените скали за определяне на риска не включват прогностичните фактори свързани с пациента, като общо здравословно състояние, наличие на коморбидитети и тяхната степен на изява. Коморбидитетите и степента на „уязвимост“ имат роля в определянето на преживяемостта при пациентите с МДС. Добавянето на коморбидните индекси като допълнителен фактор към утвърдените рискови скали значително подобрява прогнозата. Установихме ролята на клинико-биологични показатели, като най-голямо значение за хода на протичане на заболяването имат процента на миелобластите в КМ, нивата на хемоглобина, MCV тромбоцитния и левкоцитите брой, серумното желязо, ЛДХ , цитогенетичните нарушения и броя и степента на дисплазията. Доказахме, че болните с тежки форми на коморбидитети са с 50% намалена преживяемост, независимо от възрастта и рисковата група. Определянето на риска чрез скалите за стратификация на риска и коморбидността чрез коморбидните индекси значително подобрява прогностичната оценка при пациенти с МДС. Комбинирането им дава възможност за по-прецизно стратифициране на риска и определяне на прогнозата

Efficacy of Inotuzumab Ozogamicin plus Ponatinib Followed by Allogeneic Stem Cell Transplantation in a Patient with Relapsed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is an aggressive disease with poor outcomes. Despite the incorporation of tyrosine kinase inhibitors (TKIs) in the therapeutic strategies, patients who relapse after chemotherapy plus TKI have poor overall survival (OS) and less chance to proceed to hematopoietic stem cell transplantation (HSCT) which remains the only curative approach. Therefore, new drugs, such as antibody-targeted therapies alone or in combination with TKIs, offer new therapeutic options for those patients. However, the combination of inotuzumab plus ponatinib has limited application. We present a case of a patient affected by Ph + ALL with T315I mutation successfully treated after early relapse with inotuzumab plus ponatinib, followed by allogeneic HSCT and ponatinib maintenance

Long-term treatment with rilzabrutinib in patients with immune thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibodymediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of =50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts =30 × 109/L and =50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals.</p

Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia

BACKGROUND Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment

Interferons at age 50: past, current and future impact on biomedicine

The family of interferon (IFN) proteins has now more than reached the potential envisioned by early discovering virologists: IFNs are not only antivirals with a spectrum of clinical effectiveness against both RNA and DNA viruses, but are also the prototypic biological response modifiers for oncology, and show effectiveness in suppressing manifestations of multiple sclerosis. Studies of IFNs have resulted in fundamental insights into cellular signalling mechanisms, gene transcription and innate and acquired immunity. Further elucidation of the multitude of IFN-induced genes, as well as drug development strategies targeting IFN production via the activation of the Toll-like receptors (TLRs), will almost certainly lead to newer and more efficacious therapeutics. Our goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential