Antithrombotic therapy with rivaroxaban in five patients with paroxysmal nocturnal haemoglobinuria and thrombotic events

Five patients with paroxysmal nocturnal haemoglobinuria and thrombotic complications under oral antithrombotic treatment with vitamin K antagonist were switched to receive the direct oral anticoagulant rivaroxaban an factor Xa inhibitor. In all five patients haematological and biochemical parameters and adverse events were evaluated for a period of twelve months. Therapy with rivaroxaban was well tolerated in all cases and one patient showed a significant reduction of bleeding and transfusion requirement. All patients obtained a significant reduction in days of hospitalization with a consequent improvement in their quality of life after rivaroxaban treatment

Clinical characteristics and outcome of patients with autoimmune hemolytic anemia (AIHA) uniformly defined as primary by a diagnostic work-up

Primary autoimmune hemolytic anemia (P-AIHA) is a relatively uncommon and hetereogeneous disease characterized by the destruction of red blood cells due to anti-erythrocyte autoantibodies (AeAbs) in the absence of an associated disease [1–3]. Secondary AHIA is frequently associated with lymphoproliferative diseases (LD) in particular, chronic lymphocytic leukemia, aggressive or indolent lymphomas, autoimmune disorders, malignancies other than lymphoid, and infections [1,2,4]. On the hypothetical assumption that in a significant proportion of cases defined as P-AIHA the clinical heterogeneity could be due to an ignored associated disease, we retrospectively analyzed the clinical characteristics and outcome of patients with a diagnosis of P-AIHA based on a diagnostic work-up aimed at excluding or identifying an associated disease. ..

Multi‑parametric MRI in the diagnosis and scoring of gastrointestinal acute graft‑versus‑host disease

Objectives Acute gastrointestinal graft-versus-host disease (GI-aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Diagnosis relies on clinical, endoscopic, and pathological investigations. Our purpose is to assess the value of magnetic resonance imaging (MRI) in the diagnosis, staging, and prediction of GI-aGVHD-related mortality. Methods Twenty-one hematological patients who underwent MRI for clinical suspicion of acute GI-GVHD were retrospectively selected. Three independent radiologists, blinded to the clinical findings, reanalyzed MRI images. The GI tract was evaluated from stomach to rectum by analyzing fifteen MRI signs suggestive of intestinal and peritoneal inflammation. All selected patients underwent colonoscopy with biopsies. Disease severity was determined on the basis of clinical criteria, identifying 4 stages of increasing severity. Disease-related mortality was also assessed. Results The diagnosis of GI-aGVHD was histologically confirmed with biopsy in 13 patients (61.9%). Using 6 major signs (diagnostic score), MRI showed 84.6% sensitivity and 100% specificity in identifying GI-aGVHD (AUC = 0.962; 95% confidence interval 0.891–1). The proximal, middle, and distal ileum were the segments most frequently affected by the disease (84.6%). Using all 15 signs of inflammation (severity score), MRI showed 100% sensitivity and 90% specificity for 1-month related mortality. No correlation with the clinical score was found. Conclusion MRI has proved to be an effective tool for diagnosing and scoring GI-aGVHD, with a high prognostic value. If larger studies will confirm these results, MRI could partly replace endoscopy, thus becoming the primary diagnostic tool for GI-aGVHD, being more complete, less invasive, and more easily repeatable. Key Points • We have developed a new promising MRI diagnostic score for GI-aGVHD with a sensitivity of 84.6% and specificity of 100%; results are to be confirmed by larger multicentric studies. • This MRI diagnostic score is based on the six MRI signs most frequently associated with GI-aGVHD: small-bowel inflammatory involvement, bowel wall stratification on T2-w images, wall stratification on post-contrast T1-w images, ascites, and edema of retroperitoneal fat and declivous soft tissues. • A broader MRI severity score based on 15 MRI signs showed no correlation with clinical staging but high prognostic value (100% sensitivity, 90% specificity for 1-month related mortality); these results also need to be confirmed by larger studies

Anti-HLA donor-specific antibodies in allogeneic stem cell transplantation: management and desensitization protocol

The role of antibodies directed against the human leukocyte antigen (HLA) system has been well analyzed in rejection of solid organ transplantations [1, 2] and in transfusion medicine [3]. In the setting of allogeneic hematopoietic stem cells transplantation (HSCT), only in the recent years their importance has been better defined, even though anti-HLA antibodies are frequently detectable in hematologic patients, due to sensitization from multiple transfusions, usually before the introduction of online universal leukoreduction, previous transplantations, and pregnancies in female patients

Donor specific anti-HLA antibodies in Hematopoietic Stem Cell Transplantation. A stepwise project to establish a better definition of their role and a desensitization strategy

Introduction: In the setting of mismatched-hematopoietic stem cells transplantation (mmHSCT), considering the risk of graft failure (GF), the detection of antibodies directed against donor specific HLA allele(s) or antigen(s) (DSA) represents a contraindication to proceed with the same donor. In many cases, it is necessary to plan an immunosuppressive strategy to decrease DSA levels, thus reducing the risk of GF. Aim: The aim of the project was to evaluate our strategy for testing/monitoring DSAs and to define the best desensitization strategy (DS), with a prospective unicentric study, including all consecutive patients candidates for a mmHSCT. The main endpoints were as follows: 1. To determine the incidence of anti-HLA antibodies (Abs) and DSAs; 2. To define the role of DSAs against each of the HLA loci; 3. To determine the critical DSAs mean fluorescence intensity (MFI) cut-off for engraftment; 4. To determine the efficacy of the employed DS; 5. To define the correct timeframe for monitoring DSAs; 6. To determine how DSAs influence outcome in haploHSCT. In addition, we evaluated the results obtained in a retrospective, multicenter study GITMO/AIBT, coordinated by our center, involving 34 transplant centers (TC) in Italy. Methods: Anti-HLA Abs research was carried out using Luminex bead assays (Lifecode ID and LSA I/II-Immucor). The results were expressed as MFI; MFI >1000 was considered positive. If the patient had DSAs and only 1 available donor, a DS was employed, scheduled with Rituximab on day -15, two single-volume plasmapheresis procedures (PP) on days -9 and -8, intravenous immunoglobulin on day -7 and an infusion of HLA selected platelets for DSA absorption, in case of persistent Abs directed against class I HLA antigens. The DS employed was defined according to DSAs MFI and FCXM (flow cytometry cross match) results; in case of MFI >1000 and <5000, and a negative FCXM, we employed a DS without PP. In addition, the results of the GITMO/AIBT study concerning the practice of DSA monitoring and DS employed in each TC were analyzed. Preliminary data: From 2014 to 2017, 20 out of 65 patients (30.77%) showed anti-HLA Abs; 4 of them were DSAs (20%, 6.15% of total). In 2 cases, an alternative donor was selected. Two patients were treated with the DS; both obtained neutrophil engraftment. Neither DSA rebound nor other complications were observed. Results-Prospective study: Since October 2017, 22/126 patients (17.46%) showed anti-HLA Abs, 5 of them DSAs (22%, 3.9% of total); 3 of them received DS following our protocol obtaining engraftment; in 1 of the 4 patients with DSAs, both the antibodies detection and the crossmatch, before starting the conditioning regimen, showed a negative result, so a DS was not necessary. One patient died before receiving HSCT, due to disease progression. DSA detection was performed every 7 days after HSCT for the 1st month, and then 60, 180 and 365 days following HSCT. Female sex (p=0.033) and a history of previous pregnancies or abortions (p=0.009) showed a statistically significant impact on alloimmunization. Factors associated with delayed PMN engraftment were patient’s female gender (p=0.039), bone marrow as stem cell source (p=0.025), and a high HSCT-specific comorbidity index (p=0.028). In our experience, none of the analyzed variables, including the detection of anti-HLA antibodies or DSAs, influenced the risk of developing GF or PGF. 2 Multicenter study (GITMO/AIBT): Data obtained from 24/34 Italian TC showed that 382 out of 896 patients (43%) candidates for a mmHSCT had been screened. Our analysis was conducted on 771/896 patients with complete data. Of them, 322 (42%) were screened and 82 (25%) showed anti-HLA antibodies. Eighteen had DSAs (22%, 5.5% of patients screened). In 9 cases various DS were employed. In 3 cases an alternative donor was selected. Six patients were not treated, according to center policy. We found a statistically significant correlation between female sex (p=0.018) or the number of previous pregnancies (p=0.012) and anti-HLA antibodies detection. Pre-transplant blood transfusions (leucodepleted only in 87% of patients) had a statistical impact on delayed full donor engraftment (p=0.001). Conclusions: Our analyses confirm that anti-HLA Abs are frequent, with a high probability of identifying DSAs. Our DS proved successful in reducing DSAs. Currently, in our Country, there is no shared policy for anti-HLA Abs management in mmHSCT. We propose a prospective multicenter study to define and validate a consensus on DSAs management and DS to be shared with other Italian TCs, GITMO and AIBT

EFFICACY, SAFETY AND COST ANALYSIS OF SUBCUTANEOUS VS INTRAVENOUS RITUXIMAB IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH RCHOP

Introduction: Rituximab (R) in combination with cyclophosphamide, doxorubicin and prednisone (R-CHOP) is the standard of care for patients (pts) with diffuse large B-cell lymphoma (DLBCL). A subcutaneous (sc) formulation that provides a fixed dose of R is being tested in a number of studies. Results indicate that the pharmacokinetics is not inferior and the response rates comparable to those obtained with the intravenous (iv) formulation. In August 2014, the Italian Medicine Agency (AIFA) approved the sc formulation for follicular lymphoma and DLBCL. We performed a retrospective analysis at our Centre in pts with DLBCL treated with RCHOP. The aim was to evaluate the costs of the 2 different formulations of R (sc vs iv) combined with CHOP and the efficacy in terms of complete response (CR) rates and toxicity. Meth- ods: We collected data from 71 consecutive pts with untreated DLBCL who received 6 cycles of RCHOP plus 2 doses of R between January 2014 and January 2016; 35 pts received iv R (375mg/mq) and 36 sc R (1400 mg) from May 2015. We compared the direct costs of the 2 for- mulations of R, the rate of CR and of adverse events (AEs) of the two subgroups of patients. Univariate analysis was used to evaluate efficacy and toxicity. Results: The clinical characteristics were well balanced be- tween the iv and sc RCHOP groups: mean age 61 years in both groups, with a mean BSA of 1.8 (1.4-2.2); IPI score ≥3, 20% vs 30%; Ann Arbor stage III-IV, 62% vs 69%. There was no significant difference in terms of efficacy: the CR rates were 30/35 (85%) and 29/36 (83%), p=0.177, respectively. Grade ≥3 AEs (45% vs 47%) were almost all hematologic (90% in both groups) and the most common AE was grade 3/4 neu- tropenia in both groups. The cost of the treatment was 472.227€ for the iv R group and 449.870€ for sc R group; with a decrease of 4.73% only of the direct costs of R. In addition, the calculated infusion time for the sc RCHOP was 135 min compared to 240 min for the iv RCHOP; this translated into a 44% chair time reduction. Conclusions: In our analysis, the use of a sc formulation of R allowed a gain of 22.357€ in terms of only direct costs compared to the schedule with iv R, with comparable response rates and similar safety profile. Given the shorter delivery time, the sc formulation could also improve pts’ comfort and reduce the burden on health care resources. Finally, the reduction in required chair time allows for a greater number of pts to be treated daily

Multiparametric Magnetic Resonance Enterography for the Diagnosis and Staging of Intestinal Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Background: Intestinal Acute graft-versus-host disease (i-aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). The clinical diagnosis of i-aGVHD is usually based on symptoms and CT findings but a definite diagnosis is made by endoscopic biopsies. To date, there are few data on the use of magnetic resonance enterography (MRE) in this setting. We hereby investigated the value of MRE in the diagnosis of i-aGVHD. Methods: A retrospective observational study was carried out on 35 patients (16 men, 19 women; age 9-69 years) with hematologic malignancies who underwent a MRE for a suspect of i-aGvHD according to the Glucksberg criteria between 2015 and 2017. MRE examinations were performed with a 1.5 Tesla scanner (Siemens, MagnetomAvanto), equipped with 16-channels phased-array coils. We used a protocol including axial and coronal T2-weighted Half Fourier Acquisition Single Shot Turbo Spin Echo sequences, with and without fat saturation; T2 weighted axial and coronal TrueFISP sequences; DWI (Diffusion Weighted Imaging) sequences with b- values of 0, 500 and 1000; axial and coronal T1 weighted VIBE sequences, before and 70 seconds after the intravenous administration of contrast media (0.1 mmol gadolinium per kilogram of body weight, Gd-DOTA, Dotarem®, Guerbet, Aulnays-sous-Bois, France). In adult patients without contraindications, a 10 ml IV dose of hyoscine butylbromide was administered before contrast injection, in order to reduce motion artefacts. To evaluate the presence and severity of the disease, the following parameters were assessed and qualitatively scored for all intestinal segments (from stomach to rectum): a) MRI inflammation-activity including mural T2 signal (oedema), mesenteric T2 signal (oedema), gadolinium wall enhancement on T1 (vascularity), DWI signal (inflammation); b) morphologic parameters of activity and severity, including maximum wall thickness, increased number and/or size of local mesenteric lymph nodes, comb sign (mesenteric vessels dilation), presence of peritoneal effusion. Results: Out of 35 patients, 21 had a definite histologic diagnosis of i-aGVHD while in the remaining 14 patients i-aGVHD was excluded. The above MRE parameters were observed in 19 out of 21(90.5%) patients with a definite diagnosis of i-aGVHD and in none of the 14 patients in which a diagnosis of i-aGVHD was excluded. A stratified mucosal wall enhancement after gadolinium injection was found in 90% of patients. Parietal enhancement was associated with high-grade oedema of mesenteric fat tissue and comb sign in 76% of cases. In 52.4% of cases, mesenteric lymph nodes were not found. Free intra-peritoneal fluid was observed in 57.2% of patients. The most commonly involved intestinal segments were distal ileum (85.7%), mean ileum (66.6%) and proximal ileum (57.1%), followed by ascending colon and sigmoid equally (38%). Spearman's test showed a statistically significant correlation between clinical stage of i- aGVHD and mural T2 signal, number of involved intestinal segments, wall thickness, T1 enhancement, peritoneal effusion (p < .001). Conclusions: In our experience MRE parameters showed a good correlation with a definite i- aGVHD diagnosed and with the stage of disease. Therefore, in patients with a clinical suspect of i-aGVHD MRE examination may be considered in order to replace endoscopic biopsy to confirm the diagnosis

Autoimmune Hemolitic Anemia in a Boy With Inactive Ulcerative Colitis

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A 35 year single center transplant experience in chronic myeloid leukemia

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) has been considered for decades the only curative approach for patients with chronic myeloid leukemia (CML). In the tyrosine kinase inhibitors (TKIs) era, HSCT for CML has been reserved only to patients not achieving a cytogenetic remission or showing progressive disease after multiple TKI treatment lines. However, a progressive improvement in the long-term survival has been obtained in the overall HSCT population. The present study aimed at evaluating whether in CML patients transplanted at our Center over a long time period - from 1983 to 2018 - the outcome improved over time. Methods: 136 consecutive patients who underwent a transplant between 1983 and 1999 were compared to 43 patients who received the transplant between 2000 and 2018. Overall survival (OS), leukemia-free survival (LFS) and graft-leukemia-free survival (GLFS) were estimated using the Kaplan-Meier method and the log-rank test was used to compare risk factors categories. Results: Of the 179 patients [median age 35 years (range7-66)], 148 (82.7%) were in 1st or 2nd chronic phase, 25 (13.9%) in accelerated phase and six (3.4%) in blast crisis. Matched related donors and alternative donors (matched unrelated donors, cord blood or mismatched related donors) were used in 156 and 23 cases, respectively. As stem cell source, bone marrow was used in 142 patients, peripheral blood in 33 and umbilical cord blood in 4. TBI- based conditioning regimens were used in 89 patients, while in the other 90 cases irradiation-free conditioning regimens were used. Both in univariate and multivariate analysis, irradiation- free conditioning regimens (HR 1.8; 95%CI 1.1-3.0, p=.0014) and transplants performed in 1st chronic phase (accelerate phase HR 2.1; 95%CI 1.2-3.8, p=.008 - 2nd chronic phase HR 4.9; 95%CI 2.3-10.3, p=.0001 - blast crisis HR 2.5; 95%CI 1.0-6.4, p< .05) were associated with a better OS. Patients transplanted before 2000 had a worse OS (HR 6.5; 95%CI 2.7-15.5, p < .0001) and DFS (HR 2.2; 95%CI 1.0-4.8, p=.045). A trend for a worse GLFS was observed in univariate analysis (HR 1.6; 95%CI 1.0-2.7, p=0.05), in the first period of observation. Conclusions: Our single center experience confirms that higher OS, DFS and GLFS are observed in CML patients allografted in more recent years. Improvement of con- ditioning regimens, use of TBI-free conditioning regimens and supportive therapy, have presumably contributed to these results, together with the more recent strategy of close monitoring of minimal residual disease, and prompt use of TKI or donor lymphocyte infusion in case of relapse. HSCT is nowadays a safer therapeutic procedure in CML patients that should be considered timely in TKI-resistant patients to avoid progression into a more advanced disease phase. Disclosure: The authors declare no conflict of interest

Peripherally inserted central catheters in allogeneic hematopoietic stem cell transplant recipients

Central venous catheters (CVC) are essential for the management of patients with hematologic malignancies, facilitating chemotherapy infusion, antibiotics, parenteral nutrition, blood products, and blood samples collection. In this population, peripherally inserted central catheters (PICC) seem to be associated with lower complications, compared with conventional percutaneously inserted devices (CICC). Data on the PICC in allogeneic hematopoietic stem cell recipients (allo-HSCT) are limited