Prevention and treatment of cancer associated venous thromboembolism - interdisciplinary consensus.

The increasing volume of the data and experience with direct oral anticoagulants (DOACS) in the primary and secondary prevention of venous thromboembolism in oncologic patients (CAVTE) has recently lead to changes in several international guidelines. We reflect these changes within the conditions in Slovak republic. In the primary prevention of CAVTE we recognise oncosurgical patients and nonsurgical patients: hospitalised and out patients. Low molecular weight heparins are still dominant in the primary prevention of CAVTE. Regarding the treatment and the secondary prevention of CAVTE, we recommend always to consider the possibility to use DOACs as they proved to be non inferior to LMWH. However, LMWH should be prefered over DOACs as well as over warfarin (VKA) in all patients who are in a clinically unstable condition with the high risk of bleeding and/or interaction with the systemic treatment. Primarily in the patients with intraluminal tumours of the upper part of the gastrointestinal tract and genitourinary tumours with the high risk of bleeding. As for the lack of data, LMWH are still preferd also in patients with primary tumours and metastatic disease of the central nervous system and in hemato oncology.

Comparison of reduced conditionings combining fludarabine with melphalan or 3-day busulfan in patients allografted for myeloid neoplasms.

In the present study we compared outcomes of patients with myeloid neoplasms undergoing allogeneic hematopoietic stem cell transplantation after fludarabine-based regimens with melphalan (FM140) or 3-day busulfan (FB3). The FM140 and FB3 combinations were administered to 21 and 27 patients, respectively. Efforts for early reduction (from day +30 to 60) and discontinuation (until day +100 to 130) of prophylactic immunosuppression were a component of the post-transplant approach. Following FB3 patients suffered from more severe stomatitis (P = 0.013). In contrast, other manifestations of regimen-related toxicity were more frequent in the FM140 group (P = 0.048). There were no statistically significant differences in the development of graft-versus-host disease, non-relapse mortality, post-transplant remission rate, or relapse incidence. Two-year disease-free survival rates were comparable in the two cohorts (66 vs. 55 %; P = 0.751), and so were the overall survival rates (64 vs. 62 %; P = 0.715). The outcomes of allografted patients with myeloid neoplasms were comparable after the FM140 and FB3 regimens. Relatively high therapeutic response in both groups may have been influenced by early reduction and discontinuation of prophylactic immunosuppression followed by effective immunological control of the malignant clone.

Reduced relative dose intensity of primary chemotherapy does not influence prognosis of patients with Hodgkin lymphoma.

AIMS: A retrospective analysis of patients with Hodgkin lymphoma (HL) was performed to assess their outcome regarding relative dose intensity (RDI) of chemotherapy administered in primary treatment. METHODS: A total of 194 patients were divided into three groups with different RDI of primary chemotherapy (100%, 90-99% and <90%). Reduced RDI in two groups (90-99% and <90%) was caused by the delay of the interval between the administration of some chemotherapeutic courses. The probability of complete remission (CR), disease relapse, event-free survival (EFS) and overall survival (OS) as the basic parameters of patient outcome were statistically compared. RESULTS: Multivariate analysis showed here were no significant differences in probability of CR (HR 0.9, 95% CI [0.75-1.08], P=0.5), risk of relapse (HR 1.34, 95% CI [0.92-1.94], P=0.11) or death (HR 1.52, 95% CI [0.94-2.5], P=0.13). There were also no significant differences in probability of EFS (mean 13 vs. 10 vs. 12 years, P=0.17; HR 1.54, 95% CI [0.91-2.6], P=0.22) or OS (mean 15 vs. 13 vs. 14 years, P=0.13; HR 1.52, 95% CI [0.93-2.5], P=0.13). CONCLUSION: We found no significant impact of primary chemotherapy delay resulting in reduced RDI on outcome in HL patients.

Identification of e6a2 BCR-ABL fusion in a Philadelphia-positive CML with marked basophilia: implications for treatment strategy.

AIM: This is a case report of a 51 year old male with marked splenomegaly, basophilia, severe thrombocytopenia, anemia and high SFKL phosphorylation downstream of Bcr-Abl, investigated for association of the e6a2 BCR-ABL fusion gene and marked basophilia. The treatment strategy implications in patients with Philadelphia positive CML are described. METHODS: RT-PCR and sequencing were carried out on the peripheral blood leukocytes to detect the type of BCR-ABL transcript. The BCR-ABL mutational status was assessed using sequencing of the RT-PCR products. The in vitro test of sensitivity to TKIs was based on detecting inhibited phosphorylation of the Crkl and Phospho-Src family kinases (SFK, Tyr416) using immunodetection. RESULTS: The cytogenetics revealed 90% of Ph+ (Philadelphia) cells in the bone marrow aspirate with no additional clonal chromosomal abnormalities at diagnosis. This correlated with an accelerated phase of the CML. Sequencing analysis of reverse transcribed and PCR amplified BCR-ABL transcript revealed a rare e6a2 fusion, with no evidence for Bcr-Abl kinase domain mutation. Western blot analysis showed high phosphorylation (activation) of Crkl and the Src family of kinases (P-SFK). In vitro test of sensitivity of the patients' leukemic cells to imatinib demonstrated sensitivity of Bcr-Abl tyrosine kinase to imatinib, as assessed by a decrease in phosphorylated Crkl and the disappearance of P-SFK, suggesting that P-Src reflects only the Bcr-Abl-dependent Src activity. The initial treatment strategy was reduced imatinib and search for an unrelated hematopoietic stem cell donor (according to the ELN recommendations). The patient was allografted with peripheral stem cells from an HLA- identical male donor but on day +70 graft failure occurred. He was allografted again with the peripheral stem cells from an HLA-identical female donor, engrafted on day +15 and showed 100% donor chimerism with no evidence of the e6a2 BCR-ABL fusion transcript on day +30. CONCLUSION: The clinical disease course in patients with the rare e6a2 BCR-ABL transcript variant is aggressive. This may be the result of increased kinase activity due to partial loss of the guanine exchange factor/dbl-like domain which mediates the interaction with several Ras-like G-proteins involved in cell proliferation, signal transduction, and cytoskeletal organization. For the above reasons, these patients should receive stem cell transplant immediately after a short course of treatment with imatinib/ dual Src/Abl kinase inhibitor or they should be registered in clinical trials with experimental agents.

Long-term outcome of patients with peripheral T-cell lymphoma treated with first-line intensive chemotherapy followed by autologous stem cell transplantation.

BACKGROUND: Peripheral T-cell lymphomas (PTCL) are infrequent subtypes of non-Hodgkin's lymphomas. The clinical course is aggressive and the median survival is about 2-3 years. An optimal first-line chemotherapy protocol has not been established and the role of high-dose therapy with autologous stem cell transplantation (ASCT) is still unclear. AIM: To analyze the long-term outcome of unselected PTCL patients treated with intensive first-line chemotherapy with high-dose therapy and ASCT. METHOD: Here we report our experience with 29 patients with PTCL. The histological subtypes were as follows: peripheral T-cell lymphoma, not otherwise specified n=13; anaplastic large cell lymphoma (ALCL) ALK-negative n=5; ALCL ALK-positive n=3; ALCL with an unknown ALK status n=3; angioimmunoblastic lymphoma n=1; hepatosplenic lymphoma n=1; Sézary syndrome n=1; and enteropathy-associated T-cell lymphoma n=2. The median age at diagnosis was 48 years (29-64), most patients had advanced Ann Arbor stages (22 patients, 77%), IPI score ≥3 was found in 13 (45%) and PIT score ≥2 in 17 (59%) of the 29 patients. Eighteen patients received first-line high-dose therapy and autologous SCT consolidation; two patients were consolidaed with allogeneic SCT in the 1st complete remission and one patient in the 1st relapse. Ten patients with FDG-avid lymphoma were examined with integrated Positron emission tomography/ Computed tomography (PET/CT) at the time of diagnosis and after first-line therapy, two other patients were assessed with Positron emission tomography/ Computed tomography (PET/CT) only at time of restaging. RESULTS: Nineteen (66%) patients achieved complete remission, 3 (10%) partial remission and 7 (24%) patients failed the treatment. The overall response rate was 76%. PET negativity (complete metabolic response) after therapy was achieved in 8/12 (75%) individuals. After a median follow-up of 55.1 months, 14 (48.3%) patients relapsed or progressed and nine patients died (lymphoma progression). Eleven patients (50% of chemosensitive patients) survived more than 50 months. Three of the long-term survivors were treated with allogeneic SCT. The 2-year event-free survival (EFS) was 52% (95% confidence interval [CI], 0.33-0.71); the 2-year overall survival (OS) rate reached 65% (95%CI, 0.47-0.84). PET negativity was associated with a lower probability of relapse (chi-square p=0.09). CONCLUSION: Our data show that intensive first-line therapy with etoposide-doxorubicine-based regimens and ASCT consolidation may lead to long-term disease control in about a half of patients with chemosensitive PTCL. Achievement PET negativity is probably an essential prerequisite for long-term complete remission.

Comparison of new flu-bu12-tg conditioning with the standard bu-cy myeloablative regimen in patients undergoing allogeneic stem cell transplantation for acute myeloid leukemia.

AIMS: This study compares the outcomes of patients with high-risk acute myeloid leukemia (AML) who underwent allogeneic stem cell transplantation (SCT) after conditioning combining busulfan (16 mg/kg orally) and cyclophosphamide (120 mg/kg intravenously) (BU-CY) with those allografted after administration of fludarabine (150 mg/m(2) intravenously), busulfan (12 mg/kg orally) and thymoglobulin (6 mg/kg intravenously) (FLU-BU12-TG). MATERIAL AND METHODS: SCT after BU-CY and FLU-BU12-TG was performed in 21 and 10 AML patients. There were no significant differences between groups in number of patients treated in complete disease remission, gender, age, donors, CD34+, mononuclear cell (MNC) count in the graft and follow-up period. However, significantly more SCTs from unrelated (90% vs. 19%; p=0.00018) and HLA-mismatched donors (50% vs. 0%; p=0.0004) were performed in the FLU-BU12-TG group. The Cox proportional hazards model was used to assess the risk of post-transplant AML relapse and non-relapse mortality (NRM). The probability of post-transplant 2-year event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: No significant differences were found between the FLU-BU12-TG and BU-CY groups in risk of AML relapse (HR=1.036; 95% CI [0.102 - 10.47]; p=0.9), post-transplant NRM (HR=0.25; 95% CI [0.031 - 1.96]; p=0.18), 2-year EFS (89% vs. 43%; p=0.19) or OS (79% vs. 57%; p=0.23). CONCLUSION: These pilot results demonstrate the efficacy of the new FLU-BU12-TG conditioning regimen in patients allografted for high-risk AML. This conditioning might become an alternative approach in patients at high risk of severe post-transplant complications after the standard BU-CY myeloablative regimen.