Comparing the safety and efficacy of ruxolitinib in patients with Dynamic International Prognostic Scoring System low-, intermediate-1-, intermediate-2-, and high-risk myelofibrosis in JUMP, a Phase 3b, expanded-access study

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, has demonstrated durable improvements in patients with myelofibrosis. In this analysis of the Phase 3b JUMP study, which included patients aged =18 years with a diagnosis of primary or secondary myelofibrosis, we assessed the safety and efficacy of ruxolitinib in patients stratified by Dynamic International Prognostic Scoring System (DIPSS) risk categories. Baseline characteristic data were available to assess DIPSS status for 1844 of the 2233 enrolled patients; 60, 835, 755, and 194 in the low-, intermediate (Int)-1-, Int-2-, and high-risk groups, respectively. Ruxolitinib was generally well tolerated across all risk groups, with an adverse-event (AE) profile consistent with previous reports. The most common hematologic AEs were thrombocytopenia and anemia, with highest rates of Grade =3 events in high-risk patients. Approximately, 73% of patients experienced =50% reductions in palpable spleen length at any point in the =24-month treatment period, with highest rates in lower-risk categories (low, 82.1%; Int-1, 79.3%; Int-2, 67.1%; high risk, 61.6%). Median time to spleen length reduction was 5.1 weeks and was shortest in lower-risk patients. Across measures, 40%–57% of patients showed clinically meaningful symptom improvements, which were observed from 4 weeks after treatment initiation and maintained throughout the study. Overall survival (OS) was 92% at Week 72 and 75% at Week 240 (4.6 years). Median OS was longer for Int-2-risk than high-risk patients (253.6 vs. 147.3 weeks), but not evaluable in low-/Int-1-risk patients. By Week 240, progression-free survival (PFS) and leukemia-free survival (LFS) rates were higher in lower-risk patients (PFS: low, 90%; Int-1, 82%; Int-2, 46%; high risk, 15%; LFS: low, 92%; Int-1, 86%; Int-2, 58%; high risk, 19%). Clinical benefit was seen across risk groups, with more rapid improvements in lower risk patients. Overall, this analysis indicates that ruxolitinib benefits lower-risk DIPSS patients in addition to higher risk

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR

P49

Myelofibrosis with myeloid metaplasia is chronic mieloproliferative disease with ineffective erythropoiesis, dysplastic-megakaryocyte hyperplasia, and an increase in the ratio of immature granulocytes to total granulocytes. The incidence rate is 3.7–5.7 per 100,000 and the median survival is estimated to be between three and six years. The pathogenesis of myelofibrosis might be explained, in part, by a somatic point mutation on exon 14 (V617F) of the JAK2 kinase gene that is located on chromosome 9p24. However, mechanisms of regulation of microenvironment in bone marrow fibrosis are not clear. Considered that main producents of pro-fibrotic factors are the megakaryocytes and the macrophages. In this study we investigated influence of platelet factors on the cellular characteristics of the macrophages with oncogenic mutation JAK2 V617F. Materials and Methods: THP-1 cell line was modified by lentiviral modification. Two cell lines established: one with expression of JAK2 with oncogenic mutation JAK2 V617F, another wild type JAK2. Cells were cultured in RPMI-1640 containing 0.1% gentamicin, 1% l-glutamine and 10% fetal bovine serum (FBS) or 5%, 10% and 15% platelet lysate (PL). Cell lines were differentiated into the macrophages using 50 ng/ml phorbolmyristate acetate (PMA). Level of expression transforming growth factor β (TGFβ), galectin-3, matrix metalloproteinases (MMP) 2, 9, 12, 13 and tissue inhibitors of matrix metalloproteinase (TIMP) accessed by specific RT-qPCR. Results: We observed increased expression level of galectin-3, MMP-2, MMP-13 and TIMP-3 in JAK2 V617F expressing macrophages cultured with 10% FBS compare to ones with WT JAK2. Also macrophages containing mutation JAK2 V617F has increased level of expression of MMP-2, TIMP-3 and TIMP-4 when cultured with 10% platelet lysate. Also, cell line containing mutation JAK2 V617F has increased levels of expression of MMP-12 for cells cultured with 15% PL. We did not observe any significant difference in expression of TGFβ, MMP-9, TIMP-1 and -2. Conclusion: Increased levels of expression of galectin-3, MMP-12 and -13 suggest that platelet factors induce macrophages with JAK2 V617F mutation to release of profibrotic factors. On the other hand, increase of antifibrotic MMP-2 and TIMP-3 revealing complex nature of melofibrosis development and need to be analyzed further. This study confirms the idea of interaction between macrophages and platelets in pathogenesis of primary myelofibrosis

EFFECTIVENESS OF VENETOСLAX IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (LITERATURE REVIEW)

Currently we are facing a revolution in therapy of chronic lymphocytic leukemia, related to the development of novel target drugs, which have markedly improved treatment results in all groups of patients. While inhibitors of Bruton’s tyrosine kinase (ibrutinib, acalabrutinib etc.) and phosphatidylinositol-3 kinase isoforms (idelalisib, umbralisib etc.) are currently in the spotlight, much less attention is paid to antiapoptotic protein inhibitors such as venetoclax. In this review we summarize the results of venetoclax clinical studies in CLL as monotherapy and in combinations. The drug is distinguished by a high rate of complete responses and minimal residual disease eradication in high risk CLL patients, as well as a favorable toxicity profile. This makes it an ideal component of non-genotoxic regimens, aimed at the cure of the disease

The biological basis and clinical symptoms of CAR-T therapy-associated toxicites.

Currently, immunotherapy is attracting a lot of attention and may potentially become a leading approach in the treatment of cancer. One emerging therapeutic, the chimeric-antigen receptor T-cell adoptive immunotherapy (CAR-T) is showing remarkable efficacy in the treatment of several B-cell malignancies. The popularity of CAR-T has been founded on two CAR T-cell products recently approved by FDA (during 2017) in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia and B-cell lymphoma. However, their toxicities observed in clinical trials were extremely significant and in some cases even fatal with no approved algorithms for toxicity prediction being available to date. A deeper understanding of the biological basis of such complications is the key to prompt and comprehensive clinical management. Here we review the wide spectrum of effects associated with CAR T cell therapy with a major focus on the pathogenesis of cytokine release syndrome and neurotoxicity as the most common, potentially life-threatening effects of this treatment. We discuss the basis of clinical management and the existing models that predict the severity of toxicity, as well as the key factors that modulate this event. Finally, we will summarize the literature detailing universal allogenic CAR T-cells and their toxicity profile