Francesca Schieppati

Cancer Tissue Procoagulant Mechanisms and the Hypercoagulable State of Patients with Cancer.

Thrombosis is a major cause of morbidity and mortality in cancer patients. Many clinical factors contribute to the high thrombotic risk of this condition, including the type of malignancy, its disease stage, anticancer therapies, and comorbidities. However, the cancer cell-specific prothrombotic properties together with the host cell inflammatory response are important players in the pathogenesis of the cancer-associated hypercoagulability. Tissue factor (TF) is the most important procoagulant protein expressed by cancer cells, and with other cancer tissue procoagulant properties highly contributes to the procoagulant phenotype of malignant cells. Recent discoveries indicate that oncogenes determine the procoagulant protein expression, including TF, in cancer tissues. In addition, in malignancy, TF is also overexpressed by host normal blood cells triggered by cancer-derived inflammatory stimuli. As a consequence, a subclinical activation of blood coagulation is typically present in cancer patients, as demonstrated by abnormalities of circulating thrombotic biomarkers. The relevance of measuring these biomarkers to determine the patient thrombotic risk level is under active investigation. The goal is to identify the high-risk subgroups to establish more accurate and targeted anticoagulation strategies to prevent thrombosis in cancer patients. Ultimately, the clarification of specific molecular mechanisms triggering blood coagulation in specific cancer types may also indicate alternative ways to inhibit clotting activation in these conditions.

EXTRACORPOREAL PHOTOPHERESIS (ECP) FOR TREATEMENT OF ACUTE AND CHRONIC GRAFT VERSUS HOST DISEASE: AN ITALIAN MULTICENTRIC RETROSPECTIVE ANALYSIS ON 94 PATIENTS ON BEHALF OF THE GRUPPO ITALIANO TRAPIANTO DI MIDOLLO OSSEO (GITMO)

Background Extracorporeal photopheresis (ECP) is considered a valid second-line treatment for acute and chronic graft versus host disease (GVHD). Methods Ninety-four patients with acute GVHD (aGVHD) (n = 45) and chronic GVHD (cGVHD) (n = 49), retrospectively recruited in 6 Italian centers, were submitted to ECP for second-line treatment. At the time of ECP, 22 (49%) and 23 (51%) of 45 patients with aGHVD were nonresponsive and in partial remission (PR) after steroids, respectively, and all the 49 patients with cGVHD were steroid refractory. Results Forty-one (91%) of 45 patients with aGVHD achieved complete remission (CR) after ECP. Fifteen (33%) of 45 patients developed cGVHD. The CR rate in patients who started ECP being nonresponsive and in PR after steroid was 86% and 96%, respectively. After a median follow-up of 20 months (range, 2-72), 15 (33%) of 45 patients developed cGHVD and 16 (35%) of 45 patients died, in 3 cases for aGVHD. A trend for a better survival was seen among patients who started ECP in PR after steroid (80% vs 50% at 2 years; P = 0.07). Overall, 22 (45%) of 49 patients and 17 (35%) of 49 patients with steroid refractory cGHVD achieved CR and PR after ECP, respectively. After a median follow-up of 27 months, 44 (90%) of 49 patients are alive, 21 of whom (48%) are on steroid. Conclusions Extracorporeal photopheresis is confirmed as an effective second-line treatment in both aGVHD and cGVHD, because it can induce a response in more than 80% of the patients and a long-term survival in at least 50% of the cases.

Comparative study on ATG-thymoglobulin versus ATG-fresenius for the graft-versus-host disease (GVHD) prophylaxis in allogeneic stem cell transplantation from matched unrelated donor: a single-centre experience over the contemporary years

Two different rabbit anti-thymocyte globulin (ATG) formulations, thymoglobulin-ATG (tATG) and fresenius-ATG (fATG) are usually employed as prophylaxis for graft-versus-host-disease (GVHD), one of t...

Acute promyelocytic leukemia in patients aged >70 years is not rare and highly curable: a single center series of 21 unselected patients

Acute promyelocytic leukemia (APL) is considered rare in elderly patients mainly because the proportion of patients included in clinical studies was limited due to frequent comorbidities, poor clinical conditions and to their higher vulnerability to drug toxicities causing an increased rate of treatment-related mortality. APL can be cured with current treatment strategies in more than 80% of patients [1,2]; since the biological characteristics of APL in elderly patients are the same than in the younger, using current treatments, APL should be potentially highly curable also in elderly patients [3–6]. In clinical trials patients aged >70 represented only 3–9% of the entire population studied [3]. Therefore, the efficacy and safety of a standard treatment program in this subset of patients are still unclear. Recommendations to reduce the intensity of the chemotherapy combined with all-trans retinoic acid (ATRA) [4–6] or to use alternative less toxic strategies [7,8] have been proposed, but only few reports are available. Herein we report clinical data and treatment results in a cohort of 21 patients aged 70 years consecutively diagnosed between 2000 and 2016, who represented 20% of 95 APL seen in the same period at our Institution. The diagnosis was confirmed by detection of PML-RARalfa molecular rearrangement with RT-PCR. All patients received at least one dose of ATRA which was given as early as APL could be suspected on morphological grounds. Patients were treated with ATRA alone or with a combination of ATRA and idarubicin according to AIDA protocols [2,5]. Schedules and doses were adapted to the single patient based on clinical judgment. Survival was evaluated using the Kaplan–Maier method and compared using log-rank tests. The main clinical characteristics at onset, the risk category according to Sanz score [9] and the treatment administered are shown in Table 1. As to comorbidities, cardiovascular disease was present in nine patients and nine patients had a prior neoplasia, treated either with radiotherapy (rectum carcinoma (n1⁄4 1)), chemotherapy (non-Hodgkin lymphoma (n1⁄4 1)), surgery and radiotherapy (thyroid carcinoma (n1⁄4 1), breast cancer (n1⁄4 1), prostate cancer (n1⁄4 1)) or surgery only (basal cell carcinoma (n1⁄4 1), melanoma (n1⁄4 1), prostate (n1⁄4 1) and bladder (n1⁄4 1) cancer). At APL diagnosis, neoplastic disease was active in one patient with breast carcinoma. Induction treatment consisted of ATRA monotherapy (n1⁄4 6) given at 45mg/sqm/d for a median of 28 days (range 1–45). In 15 patients, idarubicin at reduced dosage, by skipping 1–3 of the four scheduled doses of 12mg/sqm was added to ATRA. There was one early death (4%) due to cerebral hemorrhage. The hematological complete remission (CR) rate was 95.2% and molecular remission rate 85.7%. ATRA-induced differentiation syndrome occurred in seven cases (33%) and was successfully managed according to common guidelines [10]. Ten infectious complications, including sepsis (n1⁄4 4), invasive aspergillosis (n1⁄4 2), Herpes Zoster Virus (HZV) reactivation (n1⁄4 1), Clostridium difficile enteritis (n1⁄4 2) and Cytomegalovirus hepatitis (n1⁄4 1) were observed in five patients. Moreover uncomplicated acute myocardial infarction occurred in one patient, four patients had deep venous thrombosis and two developed transient renal failure, not requiring dialysis. Consolidation was given to 18 of 20 patients: 17 received chemotherapy with (n1⁄4 14) or without (n1⁄4 3) ATRA and one patient ATRA only. Maintenance with ATRA 45mg/sqm/d for 15 days every 3 months plus low dose chemotherapy (methotrexate and 6-mercaptopurine) was administered for 2 years, in 16 patients. During consolidation and maintenance, non-fatal complications, including HZV reactivation (n1⁄4 1), recurrent urinary tract infections (n1⁄4 1), congestive cardiac failure (n1⁄4 1) and fever of unknown origin (n1⁄4 2), were observed. Seven patients relapsed (7/ 20; 35%), two of whom in central nervous system, after a median of 7 months (range 3–63) from CR achievement. Relapse was correlated neither to APL Sanz risk score (two relapses in low risk, three in intermediate risk and two in high risk patients, respectively), nor to the dose of idarubicin received during induction. After a median observation period of 49 months, 12 patients died, only five of them (41.6%) with active APL. One patient died of sepsis during consolidation chemotherapy in second CR and one of

Acquired cyclic neutropenia associated with cocaine-induced anti-neutrophil cytoplasmic antibodies binding to human neutrophil elastase

REFERENCES 1. Streiff MB, Milentijevic D, McCrae K, et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol 2018;93(5):664-671. 2. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a Coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349(2):146-153. 3. Lee AY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015;314(7):677-686. 4. Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D) [published online may 10, 2018]. J Clin Oncol 2018. doi: https://doi.org/10.1200/JCO.2018.78.8034, 36, 2017-2023. 5. Khorana AA, McCrae K, Milentijevic D, et al. VTE recurrence and safety of anticoagulants among patients with cancer treated for venous thromboembolism. Blood. 2017;130(Suppl 1):4631.

Lenalidomide in patients with red blood cell transfusion-dependent myelodysplastic syndrome and del(5q): a single-centre “real-world” experience

“Real life” data are needed to complement published trials on the efficacy of lenalidomide in patients with myelodysplastic syndrome (MDS) and del(5q) and on the risk of inducing acute myeloid leukemia (AML) progression. Here, we present results of lenalidomide treatment in a consecutive, population-based series of 21 red blood cell (RBC) transfusion-dependent elderly patients with multiple comorbidities. Of 18 evaluable patients (median follow-up: 22 months), 17 achieved an erythroid hematologic response (HI-E) and 16 an RBC transfusion independence. Cytogenetic response (CyR) rate was 80%, median overall survival was 48 months (range 3–164), and 5-year leukemia-free survival was 84%. Three patients progressed to AML; one, with baseline TP53 mutation, achieved HI-E, partial CyR, and did not progress to AML. Eighteen patients experienced hematological adverse events. Overall, lenalidomide was very effective and well tolerated even in unselected elderly patients with multiple comorbidities and did not appear to increase the risk of AML.