Luca Nassi

Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi

BACKGROUND The combination of rituximab, bendamustine, and cytarabine (R-BAC) was highly active in a pilot trial of mantle cell lymphoma, but its use was restricted by high haematological toxicity. We aimed to assess the efficacy and safety of an R-BAC regimen with low-dose cytarabine (RBAC500). METHODS In this multicentre, phase 2 trial, we recruited previously untreated patients with an established histological diagnosis of mantle cell lymphoma from 29 Fondazione Italiana Linfomi centres in Italy. Patients had to be older than 65 years and fit according to the comprehensive geriatric assessment, or aged 60-65 years if they were ineligible for high-dose chemotherapy plus autologous stem-cell transplantation and were fit or unfit. All patients received RBAC500 (rituximab 375 mg/m2 on day 1, bendamustine 70 mg/m2 on days 2 and 3, and cytarabine 500 mg/m2 on days 2-4; all administered intravenously) every 4 weeks for up to six cycles. Primary endpoints were the proportion of patients achieving complete response at the end of treatment and toxicity, defined as the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity. All patients who started at least one cycle of RBAC500 were included in the primary and safety analyses. Using efficacy and toxicity as a composite primary endpoint, we considered the final conclusion positive if more than 28 of 57 patients achieve complete response and fewer than 18 of 57 patients report toxicities. This study is registered with EudraCT, number 2011-005739-23, and ClinicalTrials.gov, number NCT01662050, and is completed. FINDINGS Between May 2, 2012, and Feb 25, 2014, we enrolled 57 patients (median age 71 years, IQR 67-75). 54 (95%) patients received at least four RBAC500 cycles (three discontinued because of toxicity), and 38 (67%) completed six cycles. Two (4%) had disease progression (one after the fourth cycle and one after the sixth cycle). All 52 (91%, lower limit of one-sided 95% CI 85%) remaining patients achieved complete response at the end of treatment. 23 (40%, upper limit of one-sided 95% CI 53%) of 57 patients had at least one episode of relevant toxicity. The most frequent grade 3-4 haematological toxicities were neutropenia (149 [49%] of 304 cycles) and thrombocytopenia (158 [52%]). Most treatment-related non-haematological adverse events were of grade 1-2, with the most frequent ones being fatigue (14 [25%] patients), nausea or vomiting (12 [21%]), and infusion-related reactions or tumour lysis syndrome (12 [21%]). 41 (72%) patients required a dose reduction. 12 patients died during the study, but no deaths were related to treatment. INTERPRETATION RBAC500 is an effective treatment for elderly patients with mantle cell lymphoma and, despite not meeting our prespecified safety boundary, haematological toxicity was manageable with appropriate supportive care and dose reduction. Since maintenance therapy is not required, RBAC500 could be considered an option and should be studied in phase 3 trials. FUNDING Fondazione Italiana Linfomi and Mundipharma.

Circulating tumor DNA reveals genetics, clonal evolution and residual disease in classical Hodgkin lymphoma

The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep next-generation sequencing approach for circulating tumor DNA (ctDNA), we aimed to identify the genetics of cHL in different clinical phases, as well as its modifications on treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory patients with cHL, including longitudinal samples collected under ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. ctDNA mirrored Hodgkin and Reed-Sternberg cell genetics, thus establishing ctDNA as an easily accessible source of tumor DNA for cHL genotyping. By identifying STAT6 as the most frequently mutated gene in ∼40% of cases, we refined the current knowledge of cHL genetics. Longitudinal ctDNA profiling identified treatment-dependent patterns of clonal evolution in patients relapsing after chemotherapy and patients maintained in partial remission under immunotherapy. By measuring ctDNA changes during therapy, we propose ctDNA as a radiation-free tool to track residual disease that may integrate positron emission tomography imaging for the early identification of chemorefractory patients with cHL. Collectively, our results provide the proof of concept that ctDNA may serve as a novel precision medicine biomarker in cHL.

Current use and potential role of procalcitonin in the diagnostic work up and follow up of febrile neutropenia in hematological patients

ABSTRACT Introduction: Febrile neutropenia (FN) represents a life-threatening complication in hematological malignancies. Its etiology is most often due to infections even though FN of other origins, such as tumor-related fever and non-infectious inflammation, should rapidly be ruled out. Initially, C-reactive protein and, more recently, procalcitonin (PCT) have been proposed as useful biomarkers for differential diagnosis. PCT was shown to be a good biomarker of bacterial infections and their clinical outcomes. Definition of standard cut-offs and design of PCT-guided treatment protocols remain however to be defined. Areas covered: In this review, highlights on the current clinical use of PCT and its potential role as a diagnostic tool have been discussed by a panel of physicians from different areas of expertise. We provide current clinical evidence that PCT has been shown to be a reliable biomarker to differentiate fever of bacterial origin from other causes. Moreover, the Authors convened to a round-table to discuss their ‘real-life experience’ and offer their recommendations by a Delphi survey. Expert commentary: PCT has an important clinical role in FN. Issues such as the validation of a specific decision algorithm that includes PCT to monitor antibiotic choice and treatment duration will be addressed in prospective studies.

Role of bone marrow biopsy in staging of patients with classical Hodgkin’s lymphoma undergoing positron emission tomography/computed tomography

Several studies suggested that staging bone marrow biopsy (BMB) could be omitted in patients with classical Hodgkin’s lymphoma (cHL) when a positron emission tomography/computed tomography (PET/CT) is performed at baseline.To address the concordance between BMB and PET/CT in the detection of bone marrow involvement (BMI) and the BMB role in determining the Ann Arbor stage, we retrospectively collected data on 1244 consecutive patients with cHL diagnosed from January 2007 to December 2013. One thousand eighty-five patients who had undergone both BMB and PET/CT were analyzed, comparing the Ann Arbor stage assessed with PET/CT only to that resulting from PET/CT combined with BMB.One hundred sixty-nine patients (16%) showed at least one focal skeletal lesion (FSL) at PET/CT evaluation. Only 55 patients had a positive BMB (5.1%); 34 of them presented at least one FSL at PET/CT. To the contrary, 895 out of 1030 patients with a negative BMB did not show any FSL (86.9%). Positive and negative predictive values of PET/CT for BMI were 20 and 98%, respectively; sensitivity and specificity were 62 and 87%, respectively. Fifty-four out of 55 patients with a positive BMB could have been evaluated as an advanced stage just after PET/CT; only one patient (0.1%) would have been differently treated without BMB.Our data showed a very high negative predictive value of PET/CT for BMI and a negligible influence of BMB on treatment planning, strengthening the recent indications that BMB could be safely omitted in cHL patients staged with PET/CT.

II. Challenges in the management of post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorders (PTLDs) represent a heterogeneous group of lymphoid proliferations arising as a consequence of immunosuppression (IS) in subjects who received solid organ transplant (SOT) or allogeneic stem cell transplant (aSCT). Despite their low incidence, PTLDs are always a concerning problem in a patient who has previously undergone a complex transplant procedure, with the necessity of a multidisciplinary management between the hematology team and the transplant team. The risk of PTLD depends on the type of transplant, with a probable direct relationship with the intensity and the duration of the IS. The incidence of PTLD after aSCT is about 1% but increases in patients undergoing HLAmismatched aSCT, receiving T-cell depletion or developing graft versus host disease (GvHD) [1]. Overall, SOT recipients have a higher risk of PTLD compared with aSCT patients, but the incidence is different according to the type of transplant (renal< liver<heart<multi-organ transplant such as heart–lung or liver–bowel) and according to Epstein–Barr virus (EBV) serological status of patients, with a higher risk in EBV-negative recipients [2].

Validation in a multicenter setting of Gitmo Criteria for identification of the poor mobilizer in multiple myeloma and lymphoma patients: preliminary analysis on 312 patients

PH-O008 ALLOGENEIC AND AUTOLOGOUS HSCT FOR ELDERLY PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA. AN ANALYSIS FROM ACUTE LEUKEMIA WORKING PARTY OF THE EBMT S. Giebel1,*, M. Labopin2, D. Beelen3, J. Finke4, L. Volin5, G. Ehninger6, R. Fanin7, R. Tabrizi8, D. Bunjes9, M. Potter10, J. J. Cornelissen11, A. Ganser12, D. Niederwieser13, P. Dreger14, E. J. Petersen15, A. Vitek16, M. Mohty2 1Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland, 2Hospital Saint-Antoine, Paris, France, 3University Hospital, Essen, 4University of Freiburg, Freiburg, Germany, 5Helsinki University Central Hospital, Helsinki, Finland, 6Universitaetsklinikum Dresden, Dresden, Germany, 7Azienda Ospedaliero Universitaria di Udine, Udine, Italy, 8CHU Bordeaux, Bordeaux, France, 9Universitätsklinikum Ulm, Ulm Germany, Ulm, Germany, 10Royal Marsden Hospital, London, United Kingdom, 11Erasmus MC-Daniel den Hoed Cancer Centre, Rotherdam, Netherlands, 12Hannover Medical School, Hannover, 13University Hospital Leipzig, Leipzig, 14University of Heidelberg, Heidelberg, Germany, 15University Medical Centre, Utrecht, Netherlands, 16Institute of Hematology and Blood Transfusion, Prague, Czech Republic

Population-based outcome analysis of diffuse large B-cell lymphoma in people living with HIV infection and competent individuals

The prognostic factors and outcome of 58 acquired immunodeficiency syndrome‐related diffuse large B‐cell lymphoma (AR‐DLBCL) patients from the Swiss HIV Cohort Study, diagnosed from 2004 to 2011, were compared with those of 326 immunocompetent (IC)‐DLBCL from the Hematology Division of the Amedeo Avogadro University (Italy) and the Oncology Institute of Southern Switzerland. Median follow‐up was 6 years; 5‐year overall survival (OS) was 68% (95% CI: 63%‐73%) in IC‐DLBCL and 63% (95% CI: 49%‐75%) in AR‐DLBCL (P = .220). The acquired immunodeficiency syndrome‐related lymphoma international prognostic index predicted OS in AR‐DLBCL. Among 148 patients younger than 61 years (40 AR‐DLBCL and 108 IC‐DLBCL) treated with RCHOP/RCHOP‐like regimens, 20 IC‐DLBCL and 9 AR‐DLBCL patients died and OS was not significantly different. A higher proportion of early deaths occurred in the AR‐DLBCL: indeed, 1‐year OS was 94% (95% CI: 87%‐97%) in IC‐DLBCL and 82% (95% CI: 66%‐91%) in AR‐DLBCL patients. After rituximab and active antiretroviral therapy introduction, AR‐DLBCL and IC‐DLBCL patients treated with curative intent have similar long‐term survival.

Predicting failure of hematopoietic stem cell mobilization before it starts: the Predicted Poor Mobilizer (pPM) score

Predicting mobilization failure before it starts may enable patient-tailored strategies. Although consensus criteria for predicted PM (pPM) are available, their predictive performance has never been measured on real data. We retrospectively collected and analyzed 1318 mobilization procedures performed for MM and lymphoma patients in the plerixafor era. In our sample, 180/1318 (13.7%) were PM. The score resulting from published pPM criteria had sufficient performance for predicting PM, as measured by AUC (0.67, 95%CI: 0.63–0.72). We developed a new prediction model from multivariate analysis whose score (pPM-score) resulted in better AUC (0.80, 95%CI: 0.76–0.84, p < 0001). pPM-score included as risk factors: increasing age, diagnosis of NHL, positive bone marrow biopsy or cytopenias before mobilization, previous mobilization failure, priming strategy with G-CSF alone, or without upfront plerixafor. A simplified version of pPM-score was categorized using a cut-off to maximize positive likelihood ratio (15.7, 95%CI: 9.9–24.8); specificity was 98% (95%CI: 97–98.7%), sensitivity 31.7% (95%CI: 24.9–39%); positive predictive value in our sample was 71.3% (95%CI: 60–80.8%). Simplified pPM-score can “rule in” patients at very high risk for PM before starting mobilization, allowing changes in clinical management, such as choice of alternative priming strategies, to avoid highly likely mobilization failure.

Romidepsin in relapsed/refractory T-cell lymphomas: Italian experience and results of a named patient program

Abstract Clinical trial results indicate that romidepsin, a histone deacetylase inhibitor, is a promising treatment in relapsed/refractory T-cell lymphomas (TCLs). This retrospective multicenter study was conducted in patients with relapsed/refractory TCL treated with romidepsin monotherapy through a Named Patient Program (NPP) in Italy. Principal endpoints were overall response rate (ORR), safety, and overall survival (OS). The ORR in 33 evaluable patients was 24.2% with an ORR in the cutaneous TCL of 35.7%. Global OS was 39.3% at 30 months. There were not any specific differences on hematological and extrahematological adverse events. Data from patients treated with romidepsin outside a controlled clinical trial give additional information about the clinical use, efficacy, and toxicity of the drug given to relapsed or refractory TCL patients in a real life context as TCLs are rare diseases and more information is needed. These findings suggest that romidepsin is effective and safe for heavily pretreated TCL patients.

A refined composite clinical score for the early identification of the predicted Poor Mobilizers (PM): a GITMO analysis.

Introduction: Umbilical cord blood (CB) is particularly enriched with very immature endothelial progenitors (i.e. endothelial colony forming cells, ECFC) able to promote neo-vascularization in hind limb ischemia immunodeficient mice (Schwarz TM et al. Arterioscler Thromb Vasc Biol 2012;32:e136). We previously demonstrated that CB ECFCs show scarce HLA antigen expression (Nuzzolo et al. Blood Transfus. 2014, Suppl 1:s367-74) and do no express AB0 blood group antigens. Indeed, similarly to mesenchymal cells, also the utilization of CB ECFCs could be not HLA-restricted. Here, we evaluated the revascularization potential of CB ECFCs in hind limb ischemia mouse model utilizing immunocompetent recipients. Materials (or patients) and methods: ECFCs were obtained according to Ingram et al. (Blood 2004;104:2752) and utilized after the third passage. Unilateral hind limb ischemia was induced in C57/BL6 mice as described (Biscetti F et al. Diabetes. 2010; 59:1496). Animals (n 1⁄4 20) received intramuscular injection of CB ECFCs (1x10 cells in 50 mL of PBS) into the right thigh and calf. The control group (n1⁄4 10) received only PBS. The laser Doppler perfusion analysis was performed at weekly intervals for 28 days. At weeks1 and 4 after surgery, mice were sacrificed and tissues stained with hematoxylineosin to evaluate the muscle fiber integrity score (from 0, i.e. no injury, to 100, i.e. maximum injury) by counting 50 fiber/ animal and scoring individual fibers as 0 (no injury), 1 (visible vacuolization), or 2 (disintegration) (Chan RK et al. Surgery 2006;139:236). The presence of CB ECFC injected cells was evaluated by immunohistochemistry using an anti-human CD31moAb (Dako). Plasma samples of sacrificed mice were analyzed for various angiogenic growth factors using the Bioplex pro-mouse cytokine panel at Bioplex cytomer (BioRad). Results: Overall, no limb loss was observed in treated and control animals. Nevertheless, at laser doppler analysis, the mean blood flow rate in ECFC treated mice was higher than in controls. The response was as early as day 7 and persisted until day 28 (0.4240.28 at day 7, 0.6340.42 at day 14 and 1.1040.82 at day 28, respectively). Regarding inflammatory cell infiltration, no difference were found in samples obtained from treated and control mice. At days 7, and to lesser extent at day 28, treated mice showed significantly higher number of injured fibers than controls (Figure 1a). After 7 days from injection, several human CD31þ cells were detectable in treated animals, whereas lower amount of human CD31þ cells was detectable at day 28. Finally, we found that the ECFC injected mice exhibited a a higher secretion of VEGF, bFGF, IL18, CCL9 and LIF in response to ischemia (Figure 1b). Conclusion: Overall, these data show that injected CB ECFCS were not rejected in C57/BL6 mice and contribute to revascularization and tissue repair both directly and indirectly, by stimulating the production of growth factors and chemokines in the recipients. Our findings support the utilization of CB ECFCs as allogeneic cell therapy product for untreatable critical limb ischemia. Supported by Fondi di Ateneo UCSC 2014. Disclosure of Interest: None declared.