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Background Stem Cell Mobilization and Collection Unit at Istituto Europeo di Oncologia (IEO; Milan, Lombardia) provides extracorporeal photopheresis (ECP) therapy to treat graft-vs-host disease (GvHD) using offline procedures. ECP can be administered via an integrated single device (online procedure). Total cost of performing ECP at IEO vs an integrated device was assessed using a micro-costing approach. Methods Ten offline ECP procedures for GvHD were monitored using Time-Driven Activity-Based Costing methodology, which utilized costs of resources, and time spent by patients/healthcare personnel with each resource. Details of ECP steps were recorded (pre-/post-treatment clinical evaluations, biological sampling, cannulation, apheresis, irradiation, reinfusion time). Time and cost comparisons between offline (combination of equipment/devices) and online technologies (THERAKOS™ CELLEX™ Photopheresis System) were performed. Cost variables: consumables, personnel, equipment, and laboratory tests. Personnel costs for online procedures were calculated using published time estimates and IEO hourly rates. Costs recorded in 2018 euros. Results Median duration of IEO offline ECP procedures (296 minutes) was greater than that reported for CELLEX ECP delivery (120 minutes). Total cost of offline ECP (€1134.57 [$1314.57]/procedure) was greater than that reported for online delivery (€1063.95 [$1232.74]/procedure). IEO performs ~84 ECP procedures/y, which would require ~412 hours/y vs 168 hours/y for online procedures; suggesting €5932.08 [$6873.72]/y savings with online procedures. Conclusions This assessment highlights potential resource time savings with online procedures. Time saved could allow increased activity with the same resources, at a department level. Potential non-monetary benefits include reduced time burden on patients, increased availability of hospital staff and improved patient safety.

The optimal stem cell (SC) mobilization strategy for patients with multiple myeloma (MM) remains a matter of debate. Possible approaches include low or high doses of cyclophosphamide (Cy), other chemotherapeutic agents, or granulocyte colony-stimulating factor (G-CSF) alone. The scope of the study was to compare low-dose Cy plus G-CSF versus intermediate-high-dose Cy plus G-CSF versus G-CSF alone for SC mobilization in MM, in terms of efficacy and safety. We retrospectively analyzed 422 MM patients undergoing SC mobilization in 6 Italian centers, including 188 patients who received low-dose Cy (LD-Cy group, defined as 2 g/m2), 163 patients who received intermediate-high-dose Cy (HD-Cy group, defined as ≥ 3 g/m2), and 71 patients who received G-CSF alone (G-CSF group). The median peak of circulating CD34+ cells was 77/µL in the LD-Cy group, 92/µL in the HD-Cy group, and 55/µL in the G-CSF group (P = .0001). The median amount of SCs collected was 9.1 × 106/kg, 9.7 × 106/kg, and 5.6 × 106/kg in the 3 groups, respectively (P = .0001). The rate of mobilization failure (defined as failure to collect ≥2 × 106/kg) was 3.7% in the LD-Cy group, 3.4% in the HD-Cy group, and 4.3% in the G-CSF group (P = .9). The target SC dose of at least 4 × 106/kg was reached in 90.4%, 91.1%, and 78.6% of the patients in these 3 groups, respectively (P = .014). The "on demand" use of plerixafor was higher in the G-CSF group (76%) compared with the LD-Cy group (19%) and the HD-Cy group (6%). In multivariate analysis, G-CSF mobilization and previous use of melphalan or radiotherapy were independently associated with failure to collect the target SC dose of ≥4 × 106/kg. No impacts of age, blood counts, or previous treatment with lenalidomide, bortezomib, or carfilzomib were observed. Our results suggest that LD-Cy may be considered for successful SC mobilization in patients with MM.

Given the availability and efficacy of the mobilizing agent plerixafor in augmenting hematopoietic progenitor cell mobilization with granulocyte colony-stimulating factor (G-CSF), there is a strong case for comparing the cost-effectiveness of mobilization with G-CSF + cyclophosphamide versus G-CSF alone. This study investigated the cost and effectiveness (i.e., successful 4 million-CD34+ collection) of G-CSF alone versus high-dose cyclophosphamide (4 g/m2) + G-CSF mobilization (± on-demand plerixafor) in patients with multiple myeloma (MM) eligible for autograft in Italy. A decision tree-supported cost-effectiveness analysis (CEA) model in MM patients was developed from the societal perspective. The CEA model compared G-CSF alone with cyclophosphamide 4 g/m2 + G-CSF (± on-demand plerixafor) and was populated with demographic, healthcare and non-healthcare resource utilization data collected from a questionnaire administered to six Italian oncohematologists. Costs were expressed in Euro (€) 2019. The CEA model showed that G-CSF alone was strongly dominant versus cyclophosphamide + G-CSF ( ± on-demand plerixafor), with incremental savings of €1198.59 and an incremental probability of a successful 4 million-CD34+ apheresis (+0.052). Sensitivity analyses confirmed the robustness of the base-case results. In conclusion, chemotherapy-free mobilization (± on-demand plerixafor) is a “good value for money” option for MM patients eligible for autograft.

Background Upfront single or tandem ASCT still represents an integral part of treatment for patients with multiple myeloma. The combination of intermediate dose (ID) - cyclophosphamide plus G-CSF, has been considered the standard method as mobilization regimen. No prospective randomized clinical trials have compared efficacy and costs using ID - cyclophosphamide against a chemo-free mobilization strategy with G-CSF and plerixafor on demand. Methods A prospective single arm of 20 patients enrolled in three Italian Centers mobilized with G-CSF plus plerixafor on demand was compared with a retrospective historical control arm of 30 patients mobilized with ID - cyclophosphamide (4 g/sqm) and G-CSF. Costs of the prospective arm was compared with the ones of the retrospective control arm with the aim to collect ≥4 × 106/kg CD34 + . The exploratory cost analysis was performed using microcosting specific inputs of G-CSF plus plerixafor on demand versus ID - cyclophosphamide + G-CSF considering pre-apheresis, peri-apheresis and post-apheresis session. Results Mobilization with ID - cyclophosphamide and G-CSF resulted in a significantly higher CD34+ peak mean on day 1 yield (119 CD34+ μL vs 67.3; p = 0.06) and in total average CD34+ yield (mean collection 10.6 × 106/kg vs 5.8 × 106/kg; p = 0.004) compared to patients mobilized with G-CSF and plerixafor. There was no significant differences (p = 0.36) in the two groups of patients collecting ≥ 4 million CD34+/Kg with ID - cyclophosphamide and G-CSF (93.3 %) vs G-CSF and plerixafor (90.0 %). None of the patients undergoing G-CSF and plerixafor mobilization had febrile neutropenia compared with 7 patients who received ID - cyclophosphamide and G-CSF (0% vs 23 %, p = 0.03) who had a median of 5 days hospitalization (range 4–6). All patients proceeded to ASCT with a mean of 3.6 CD34+/kg infused for G-CSF and plerixafor arm and 4.4 CD34+/kg for the ID - cyclophosphamide + GCSF group (p = 0.37) with a median time to ANC and PLT engraftment not different in the two groups. Total costs of a mobilizing strategy using a combination of G-CSF and plerixafor on demand was 12.690 euros compared to 16.088 euros with ID - cyclophosphamide and G-CSF (p = 0.07); in particular, mobilization cost components were significantly lower for G-CSF and plerixafor vs G-CSF and ID - cyclophosphamide for hospital stay (3080 euros vs 9653 euros; p Conclusions Our data demonstrate that in patients with multiple myeloma eligible for ASCT, a chemo-free mobilization with G-CSF and plerixafor on demand is associated with efficacy in PBSC collection and optimal safety profile with similar average costs when compared to a chemo-mobilization with ID - cyclophosphamide. A prospective randomized multicenter study could address which is the most cost-effective strategy for this setting of patients. Clinical Trial Registry Eudract Number EudraCT 2013−004690-27.

In a retrospective analysis of data from 13 European Society for Blood and Marrow Transplantation (EBMT) centers, we evaluated the contemporary outcomes of high-dose chemotherapy (HDCT) as salvage therapy of advanced seminoma. The results supported the use of HDCT, particularly for patients with chemosensitive disease. This proof of concept needs to be prospectively validated in a randomized trial of HDCT versus standard-dose chemotherapy. Background: The optimal management of advanced seminoma that relapses after chemotherapy remains unknown. We retrospectively analyzed outcomes with the use of high-dose chemotherapy (HDCT). Patients and Methods: Eligibility included adult male patients with pure seminomatous histology and treatment with salvage HDCT. Data of patients who received HDCT from 13 European Society for Blood and Marrow Transplantation (EBMT) centers were used. Multivariable Cox analyses evaluated the association of prespecified factors (line of treatment, prior radiotherapy, and chemosensitivity according to standard definition), with progression-free (PFS) and overall survival (OS). The prognostic ability of the model was assessed through the concordance statistic. Results: From December 2002 to December 2012, 46 cases were identified. Median age was 38 years (interquartile range, 35-46 years). HDCT was provided as second-line therapy (n = 14, 30.4%) and in third-line or beyond third-line therapy (n = 20, 43.5%; 12 had missing information). Sixteen patients (34.8%) received paraortic and/or iliac radiotherapy, and 10 (21.7%) had disease that was cisplatin refractory or absolutely refractory. Median follow-up was 22 months (interquartile range, 8-56). On multivariable Cox analysis, refractory disease was a significantly negative prognostic factor for both PFS (hazard ratio, 6.04; 95% confidence interval, 1.86-19.64) and OS (hazard ratio, 3.93; 95% confidence interval, 1.07-14.45), while prior radiotherapy trended to significance for both. The c index was 0.74 and 0.66 for PFS and OS, respectively. The small numbers and the lack of any comparison with conventional-dose chemotherapy are major study limitations. Conclusion: Despite our small sample size, this retrospective analysis suggested that HDCT may represent a valuable therapeutic option for patients with a pure seminoma after standard-dose chemotherapy failure. Our observation requires validation through a prospective study.

Collection of HPC by apheresis requires adequate venous access for inflow and for outflow. The use of midline has never been reported in this setting. We prospectively analyzed the use of midline for performing apheresis on 3 healthy donors and 3 adults patients requiring autologous transplantation. A total of 8 polyurethane midlines, with an external diameter of 5 French, was inserted (2 midlines in both arms in 2 healthy donors) by our PICC team the day before apheresis and removed at the end of target collection. Mean flow rate was 35 ml/min. Target cellular dose was reached in all patients / donors with a maximum of 2 procedures without any complications. Midline is effective and safe for HPC collection either in donors or patients avoiding the placement of a central venous catheter.

The recent SARS-CoV-2 pandemic is a new challenge for clinicians worldwide. Although the clinical aspects are well described by different groups, there are still some areas of uncertainty about the interpretation of diagnostic methods. Herein, we describe the clinical case of a 45-year-old lady that contracted SARS-CoV-2 infection with a prolonged PCR positive nasopharyngeal swab but lack of COVID-19 defining events.

Chronic hepatitis C virus (HCV) infection is related with an increased risk of non-Hodgkin lymphomas (NHL). In indolent subtypes, regression of NHL was reported after HCV eradication with antiviral therapy (AT). In 2008 in Lombardy, a region of Northern Italy, the "Rete Ematologica Lombarda" (REL, Hematology Network of Lombardy-Lymphoma Workgroup) started a prospective multicenter observational cohort study on NHL associated with HCV infection, named "Registro Lombardo dei Linfomi HCV-positivi" ("Lombardy Registry of HCV-associated non-Hodgkin lymphomas"). Two hundred fifty patients with a first diagnosis of NHL associated with HCV infection were enrolled; also in our cohort, diffuse large B cell lymphoma (DLBCL) and marginal zone lymphoma (MZL) are the two most frequent HCV-associated lymphomas. Two thirds of patients had HCV-positivity detection before NHL; overall, NHL was diagnosed after a median time of 11 years since HCV survey. Our data on eradication of HCV infection were collected prior the recent introduction of the direct-acting antivirals (DAAs) therapy. Sixteen patients with indolent NHL treated with interferon-based AT as first line anti-lymphoma therapy, because of the absence of criteria for an immediate conventional treatment for lymphoma, had an overall response rate of 90%. After a median follow-up of 7 years, the overall survival (OS) was significantly longer in indolent NHL treated with AT as first line (P = 0.048); this confirms a favorable outcome in this subset. Liver toxicity was an important adverse event after a conventional treatment in 20% of all patients, in particular among DLBCL, in which it is more frequent the coexistence of a more advanced liver disease. Overall, HCV infection should be consider as an important co-pathology in the treatment of lymphomas and an interdisciplinary approach should be always considered, in particular to evaluate the presence of fibrosis or necroinflammatory liver disease.

There are no widely accepted prognostic indices for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). This study aimed to develop and validate a specific prognostic tool to personalize and optimize treatment of patients with MALT lymphoma. A prognostic index was built by Cox regression (stepwise selection) using data from 401 patients enrolled in the international randomized International Extranodal Lymphoma Study Group 19 (IELSG-19) trial (NCT 00210353). A validation set, including 633 patients, was obtained by merging 3 independent cohorts of MALT lymphoma patients. The 3 individual features maintaining the greatest prognostic significance for event-free survival (EFS, the main endpoint of the IELSG-19 trial) were age ≥70 years (hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.26-2.33), Ann Arbor stage III or IV (HR, 1.79; 95% CI ,1.35-2.38), and an elevated lactate dehydrogenase level (HR, 1.87; 95% CI, 1.27-2.77). The prognostic index (MALT-IPI) constructed using these 3 parameters identified 3 groups: low, intermediate, and high risk (corresponding to the presence of 0, 1, or ≥2 of these factors, respectively). The 5-year EFS rates in the low-, intermediate-, and high-risk groups were 70%, 56%, and 29%, respectively. The MALT-lymphoma International Prognostic Index (MALT-IPI) also significantly discriminated between patients with different progression-free, overall, and cause-specific survival. The prognostic utility was retained in gastric and nongastric lymphomas, in each treatment arm (chlorambucil, rituximab, and rituximab plus chlorambucil), and was confirmed in the validation set. The new index, MALT-IPI, is a simple, accessible, and effective tool to identify MALT lymphoma patients at risk of poor outcomes. It may help define appropriate treatment approaches for individual patients.

Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Current evidence suggests that the addition of plerixafor with chemotherapy plus G-CSF is safe and effective in the large majority of the patients with low blood CD34(+) cell count after mobilization and/or poor yield after the first collection. Nevertheless, there are several questions strongly debated, and in this paper, we would like to identify areas of possible future use and development of the drug.

Stem cell (SC) mobilization is significantly influenced by the mobilization schedule in patients with lymphoma. We evaluated data from 30 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) undergoing SC mobilization. All received R-ESHAP plus a single dose of pegfilgrastim. All patients collected ⩾2×10 6 CD34+cells/kg, 80% of them at least 5×10 6 CD34+cells/kg. Adverse effects of the regimen included myelosuppression and neutropenic fever. Herein, our results suggest that R-ESHAP plus pegfilgrastim is a highly effective mobilization strategy in patients affected by DLBCL associated with a low incidence of adverse events.

PubMed ID: 26642334 Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty-one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P

Extracorporeal photopheresis (ECP) is considered a valid second-line treatment for acute and chronic graft versus host disease (GVHD).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.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.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.

Patients with a number of peripheral CD34+ cells ≥20/μL have recently been defined in the literature as "poor mobilizers". We retrospectively reviewed medical records from a total of 248 patients affected by hematological malignancies or solid tumors undergoing peripheral blood stem cell collection following chemotherapy plus G-CSF. On the basis of the CD34+ cell peak in peripheral blood following mobilization therapy, patients were defined as good mobilizers (group A, CD34+ cells ≥20/μL), relative poor mobilizers (group B, CD34+ cells20 and ≥8/μL) and absolute poor mobilizers (group C, CD34+ cells8/μL). One hundred and seventy-seven (71%) patients resulted good mobilizers, 35 (14%) patients relative poor mobilizers and 36 (15%) patients absolute poor mobilizers. Target of stem cell collection was ≥2.0×10(6) CD34+cells/kg for each transplantation procedure. All patients in group A, 20 patients in group B (57%) and 1 patient in group C (2.7%) were able to collect ≥2.0×10(6) CD34+cells/kg. The multivariate analysis confirmed that more than three lines of previous chemotherapy and a previous autologous PBSC transplantation negatively affect mobilization of CD34+ cells in peripheral blood. Our data suggest that a number of CD34+ cells ≥20/μL does not always result in a failed stem cell collection and in fact in our patient series more than 70% of the patients defined as poor mobilizers have indeed collected the minimum number of 2.0×10(6) CD34+cells/kg required for a successful transplantation. The use of new agent such as CXCR4 antagonist plerixafor might further improve mobilization efficacy in such patients.

Purpose Rituximab maintenance therapy has been shown to improve progression-free survival in patients with follicular lymphoma; however, the optimal duration of maintenance treatment remains unknown. Patients and Methods Two hundred seventy patients with untreated, relapsed, stable, or chemotherapy-resistant follicular lymphoma were treated with four doses of rituximab monotherapy in weekly intervals (375 mg/m2). Patients achieving at least a partial response were randomly assigned to receive maintenance therapy with one infusion of rituximab every 2 months, either on a short-term schedule (four administrations) or a long-term schedule (maximum of 5 years or until disease progression or unacceptable toxicity). The primary end point was event-free survival (EFS). Progression-free survival, overall survival (OS), and toxicity were secondary end points. Comparisons between the two arms were performed using the log-rank test for survival end points. Results One hundred sixty-five patients were randomly assigned to the short-term (n = 82) or long-term (n = 83) maintenance arms. Because of the low event rate, the final analysis was performed after 95 events had occurred, which was before the targeted event number of 99 had been reached. At a median follow-up period of 6.4 years, the median EFS was 3.4 years (95% CI, 2.1 to 5.3) in the short-term arm and 5.3 years (95% CI, 3.5 to not available) in the long-term arm (P = .14). Patients in the long-term arm experienced more adverse effects than did those in the short-term arm, with 76% v 50% of patients with at least one adverse event (P < .001), five versus one patient with grade 3 and 4 infections, and three versus zero patients discontinuing treatment because of unacceptable toxicity, respectively. There was no difference in OS between the two groups. Conclusion Long-term rituximab maintenance therapy does not improve EFS, which was the primary end point of this trial, or OS, and was associated with increased toxicity.

Plerixafor, a CXCR4 antagonist, has shown to be effective in increasing the number of circulating stem cells, even in patients failing a previous mobilisation attempt. Recently a number of non-glycosylated recombinant human granulocyte-colony stimulating factor (G-CSF) has been clinically approved for the same indications as the originator G-CSF for comparable safety and efficacy and their reduced cost. In an attempt to provide a less toxic strategy, 14 patients affected by haematological malignancies (non-Hodgkin's lymphoma = 4, Hodgkin's disease = 2 and multiple myeloma = 8), received the combination of biosimilar filgrastim and plerixafor as a first line mobilising strategy. The median number of circulating CD34+ cells on day 4 was 16 (3-42); Plerixafor was administered to all, but one patient who had already 42 CD34+ cells per μL on day 4. On day 5, after plerixafor administration, the median number of circulating CD34+ cells had raised to 60 per μL (14-138). All the patients underwent leukapheresis and were able to collect a number of CD34+ cells ≥ 2.0 × 10(6) /kg in a median number of procedures of one. Although preliminary, these data show the combination of biosimilar filgrastim and plerixafor is effective and provides a non-toxic approach to mobilise stem cells.

Background: Follicular lymphoma is usually a disase with a prolonged course and a chemotherapy-free regimen might be a favourable treatment strategy. SAKK 35/03 investigated two different durations of rituximab maintenance (5 years vs. 6 months) in patients with follicular lymphoma after induction with 4 weekly doses of rituximab monotherapy. With a median follow-up of 6.4 years we were not able to show a benefit with long-term rituximab maintenance up to five years in event-free survival (EFS) or overall survival (OS ). Here we report the final results with a median follow-up of 10 years. Methods: 270 patients (median age 57 years: range 25-82) with untreated, relapsed, stable or chemotherapy resistant follicular lymphoma were treated with 4 doses of rituximab monotherapy in weekly intervals (375 mg/m²). Patients achieving at least a partial response were randomly assigned to receive maintenance therapy with one infusion of rituximab every 2 months, either on a short-term schedule (four administrations) or a long-term schedule (maximum of five years or until disease progression or unacceptable toxicity). The primary endpoint was EFS . Progression-free survival (PFS), OS, and toxicity were secondary endpoints. Comparisons between the two treatment arms were performed using the log-rank test for survival endpoints. Results: 165 patients were randomly assigned to short-term (n=82) or long-term (n=83) maintenance. At a median follow-up period of 10 years, the median EFS is 3.4 years (95% CI 2.1-5.5) in the short-term arm and 5.3 years (95% CI 3.5-7.5) in the long-term arm. Using the pre-specified log-rank test this difference is statistically not significant (p=0.39 ). There is no significant difference in PFS and OS. Median OS in the short-term arm is 11.0 years (95% CI 11.0, NA ) and not reached in the long-term arm (p=0.80). The incidence of subsequent cancers increased in both arms over time, nine patients developed a subsequent cancer in the short-term maintenance arm and 10 in the long-term maintenance arm. There was no major additional toxicity with longer follow-up. Conclusions : Even with a long follow-up of 10 years we were not able to show a significant benefit of long-term compared to short-term rituximab maintenance in EFS, PFS and OS. Treatment strategies and study designs need to take these results into consideration in order to guarantee optimal medical and scientific results. Disclosures Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Background: haploidentical hematopoietic stem cell transplant (HSCT) with post-transplant cyclophosphamide (Cy) is a procedure for patients with advanced haematological malignancies lacking an HLA identical donor. Even if several groups reported interesting results about allograft in lymphoma, the current clinical practice doesn't include routinely allogeneic stem cell transplantation in patients with suboptimal response to salvage strategies. A prospective study based on the use of peripheral blood stem cells (PBSC) as graft source was launched at European Institute of Oncology in 2010. The aim of this paper is to report the results of haplo-HSCT in patients with relapsed and refractory lymphoma with detectable disease before transplant. Patients and Methods: between June 2010 and May 2018, 64 have been enrolled in the study at our institute; the updated experience of 35 patients affected by high risk lymphomas is reported.Haploidentical HSCT was performed with G-CSF mobilized PBSC. Conditioning regimen was either non-myeloablative (31 patients) (Cy 14.5 mg/kg/die days -6,-5, fludarabine 30 mg/m2/die days -6 to -2, and 200 cGy Total Body Irradiation day -1), or myeloablative (treosulfane 14 mg/m2/die days -6 to -3 and fludarabine 30 mg/m2/die days -6 to -2). GVHD prophylaxis consisted of post-transplant cyclophosphamide (50 mg/kg day +3 and +4) and mycophenolate and tacrolimus as previously described.Among 35 evaluable patients, 28 (80%) performed haplo-HSCT for refractory/relapsed non-Hodgkin lymphoma; the remaining patients included 7 relapsed and refractory Hodgkin lymphoma. Median age was 52 (19-73), disease status included 13 (37%) complete remission (2 CR1, 11 CR≥2), 9 (26%) partial response (PR), 4 (11%) stable disease (SD), 9 (25%) progressive disease (PD). A median of 5.5 x106(range 2.45 -13.4) CD34+ cells/kg was infused, with a median of 2.8x108(range 0.3-5.4) CD3+ cells/kg. Median lines of previous treatment: 3 (0-7). Results: four deaths due to infections have been recorded before engraftment. Among all 64 evaluable patients, median time to absolute neutrophils ≥500/µL was 18 days (range 12-29), and 23 days (range 11-65) to platelets ≥20.000/µL. Incidence of grade I-II acute GVHD was 22%, with grade III of 2%. Mild chronic GvHD was observed in 7/60 evaluable patients (1-year cumulative incidence: 13 %). Mixed donor chimerism was achieved in all 60 evaluable patients, with CD3+ chimerism >50% at day +28, >90% at day + 84. No graft failure has been recorded. CMV reactivation occurred in 77% of lymphoma patients (27/35 subjects at risk), at a median of 35 days (range 5-50) post-HSCT; pre-emptive therapy was effective in all patients. Regarding the lymphoma population, with a median follow-up of 360 days (6-2,460), 19 patients are alive (54%), 18 of them (51% of the whole series) in CR, while the cumulative incidence of relapse is 25%; when disease status at transplant is considered, the incidence of relapse at 2 years is 4% and 54% for chemo-sensitive and chemo-refractory, respectively (see graphic 2 in figure 1). Overall, 16 patients (45%) died; causes of death were PD in 8 patients (50%), infections in 8 (50%) with a cumulative transplant related mortality of 45%. The 3-year PFS and OS for the all lymphoma patients is 58% and 54%, respectively, with 81% and 66% for patients transplanted in CR/PR and 32 % and 31% for those transplanted in SD/PD (p-value 0,001 Log-rank - graphic 1 in figure 1). Conclusions: Haploidentical T-cell replete PBSC transplantation with high-dose post-transplant Cy is a feasible procedure for high-risk haematological malignancies, with an overall toxicity analogous to HSCT with HLA-identical donors. Despite the small study population, haplo-HSCT seems to be an effective strategy even in patients with active lymphoma before transplant. As previously reported, chemosensitive (CR/PR) patients have a better outcome compared to chemo-refractory cases. However, the latter population still may have a benefit from haplo-HSCT as suggested by our data, thus the cellular therapy strategy should not be discouraged in presence of disease (SD/PD). Our future purpose is to enhance the graft versus lymphoma effect with Natural Killer cells infusions. This option will be soon developed at our hospital within a prospective trial. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Purpose To assess the efficacy of 2-chloro-2′-deoxyadenosine (2-CdA) given subcutaneously (SC) in combination with rituximab in the treatment of newly diagnosed/pretreated patients with Waldenström macroglobulinemia (WM) and to correlate the response to treatment with biologic findings (immunophenotypic and pharmacogenomic analysis). Patients and Methods From December 2003 to February 2007, 29 patients were enrolled. Intended therapy consisted of a combination of rituximab (375 mg/m2) on day 1 followed by 2-CdA 0.1 mg/kg (SC injection) for 5 consecutive days, administered monthly for four cycles. Anemia (n = 16), neurologic symptoms (n = 6), symptomatic cryoglobulinemia (n = 4), and thrombocytopenia (n = 3) represented the reasons for starting treatment. The expression of ζ chain–associated protein kinase 70 (Zap-70) and of seven genes involved in 2-CdA metabolism as markers of response to the combination treatment was evaluated. Results With a median follow-up of 43 months, the overall response rate observed was 89.6%, with seven complete responses (CR), 16 partial responses, and three minor response, without any difference between newly or pretreated patients (P = .522). The therapy was well tolerated, except for transitory cardiac toxicity (n = 2) and intolerance to rituximab (n = 2). No major infections were observed despite the lack of antimicrobial prophylaxis. No patients developed transformation to high-grade non-Hodgkin's lymphoma nor myelodysplasia. Low expression levels of human concentrative nucleoside transporter 1 (hCNT1) were correlated with the failure to achieve a CR (P = .024), whereas no association with Zap-70 expression was found. Conclusion The combination of rituximab and SC 2-CdA is safe and effective in patients with WM requiring treatment. The pharmacogenomic analysis associated with the study suggests hCNT1 might be beneficial in predicting clinical response to such a combination treatment.

Purpose Resistance to nucleoside analogues agents is likely to be multifactorial and could involve a number of mechanisms affecting drug penetration, metabolism and targeting. In vitro studies of resistant human cell lines have confirmed that human concentrative nucleoside transporter 1 (hCNT1)-deficient cells display resistance. Experimental design We applied real-time PCR method to assess the mRNA expression of equilibrative and concentrative nucleoside transporter (hENT1, hCNT1), deoxycytidine and deoxyguanosine kinase (dCK, dGK), 5′-nucleotidase (5′-NT), ribonucleotide reductase catalytic and regulatory (RR1, RR2) subunits in bone marrow cells from 32 patients with Waldenstrom's Macroglobulinemia (WM) and small lymphocytic lymphoma (SLL) who received 2CdA-based chemotherapy. Responses to chemotherapy, were then correlated to the expression of these markers. Results All 32 patients enrolled expressed lower levels of hCNT1 as compared to healthy donors. In univariate analysis, lower expression level of hCNT1 ( p = 0.0021) and RR2 ( p = 0.02) correlated with response to chemotherapy. In particular, patients with low levels of hCNT1 achieved inferior clinical response. No significant correlation between these genes expression and age, stage of disease was found. This study suggests that nucleotidase expression levels can be used to identify subgroups of WM and SLL patients who will likely respond differently to a 2CdA-based therapy.

Second allogeneic hematopoietic stem cell transplantation (HSCT2) is a frequently used treatment option for relapse of acute leukemia after first allogeneic transplantation. Remission can be induced in selected patients, but data on long-term outcome and finally cure are limited. To estimate the long-term results of HSCT2, we retrospectively analyzed the course of 286 patients receiving myeloablative HSCT2 between 1985 and 2000, with a median follow-up of 11.3 years. Overall survival (OS) and leukemia-free survival (LFS) at 10 years from HSCT2 were 10±2 and 7±2%, respectively. Cumulative 10-year incidence of relapse and non-relapse mortality were 58±3% and 35±3%, respectively. CR at HSCT2, an interval from first transplant to relapse >10 months and TBI as part of the conditioning for HSCT2 favorably influenced LFS and OS. Patients with all three favorable factors had a 10-year OS of 36±10% and LFS of 25±9%, whereas patients showing no favorable factor had all died before year 5. Although retrospective, the long follow-up of this analysis supports the curative potential of alloHSCT2 in selected patients, who might be identified in advance, based on prognostic factors.

An abnormal expression of cyclin D3, a key regulator of the cell cycle, has been documented in a variety of human malignancies, and the cyclin D3 gene, mapping to 6p21, may be deregulated in plasma cell myeloma and non-Hodgkin's lymphoma as a result of the t(6;14)(p21.1;q32.3) translocation and/or gene amplification. In the current study, we for the first time investigated by immunohistochemistry and fluorescence in situ hybridization (FISH) the prevalence of cyclin D3 abnormalities in follicular lymphomas (FLs), comparing the results with traditional clinicopathologic characteristics, p27 and skp2 immunoreactivity (IR) and Ki-67 labeling index (LI). Cyclin D3, skp2 and Ki-67 IR significantly increased from grade I to grade III FL (p = 0.0003, p = 0.0001 and p < 0.0001, respectively), while p27 IR was significantly (p < 0.0001) more prevalent in low-grade tumors. Cyclin D3 IR was directly correlated with the Ki-67 LI (p < 0.0001) and inversely correlated with p27 IR (p = 0.050). None of the 13 cases analyzed by FISH showed the t(6;14) translocation, but in 2 (15.3%) grade I FLs 3 cyclin D3 signals were detected. Cohybridization with probes specific for the centromeric region and the long arm of the chromosome 6 indicated trisomy in one case and a pattern highly suggestive for the presence of an isochromosome 6p in the other case. Our data suggest that the t(6;14) translocation may be extremely uncommon in FL and that a deregulated expression of cyclin D3, possibly due to epigenetic mechanisms, may be involved in the pathogenesis of high-grade tumors.

Treatment of acute leukaemia in adult Jehovah's Witnesses (JW) is challenging because of 'a priori' refusal of most physicians to apply diagnostic and therapeutic procedures to haematological abnormalities resembling acute leukaemia. Rejection of blood transfusions by individuals of this faith is usually blamed to justify this attitude, thus leading to severe personal, medical and psychological distress related to the lack of care. We therefore intended to verify whether a standard (tailored) chemotherapy, without the use of prophylactic blood product transfusions, could be applied during treatment of acute leukaemia under such circumstances. Eleven consecutive JW adult patients with acute leukaemia, all of whom had been denied care in other institutions, were treated at the European Institute of Oncology (EIO) in Milan, Italy. Five had acute lymphoblastic leukaemia (ALL) (one bcr/abl positive), six had acute myeloid leukaemia (AML) with immunophenotype and/or cytogenetic intermediate-high risk features, except one patient with acute promyelocytic leukaemia (APML). Standard induction chemotherapy [cytosine arabinoside (ARA-C) and daunorubicin (DNR) for AML, vincristine (VCR), DNR and prednisone (PDN) for ALL, all-trans retinoic acid (ATRA) and DNR for APML] with the antracycline dose of at least 30 mg/sqm were used. All patients experienced severe anaemia after induction chemotherapy despite erythropoietin. Median haemoglobin nadir for patients with ALL and AML was 4.5 g/dL (range 1.3-6.9) and 5.1 g/dL (range 2.6-6.8), respectively. Median platelet nadir counts for all patients was 14.5 x 10(9))/L (range 1-24). One patient died during induction probably due to haemorrhage. Four of five patients with ALL achieved a complete remission (CR) (including the bcr/abl case) while among patients with AML only the one with APML achieved CR. Three patients (APML = 1 and ALL = 2) are still alive and disease-free. This small series of adult patients with leukaemia illustrates difficulties in treating patients who are practising JW, yet nevertheless provides a significant argument against the prejudicial decision leading to evasion of treatment in these patients.

We investigated the toxicity and efficacy of the chimaeric anti-CD20 antibody rituximab in combination with standard-dose chlorambucil in newly diagnosed and relapsed/refractory indolent B-cell lymphoma patients. A total of 29 patients (15 newly diagnosed and 14 relapsed/refractory) with low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) were included in this phase II study. Therapy consisted of chlorambucil 6 mg/m2/d for 6 consecutive weeks in combination with a standard 4-weekly rituximab administration schedule in the induction phase. Patients responding to the induction therapy received four additional cycles with chlorambucil (6 mg/m2/d for 2 weeks/month) plus rituximab (once a month). Twenty-six patients (89%) completed the treatment; only one patient discontinued treatment because of haematological toxicity. At the end of the study, the dose of chlorambucil had to be reduced in seven patients (27%) and six patients (23%) required a delay in further treatment, as a result of toxicity during consolidation therapy. Only one patient was withdrawn from the study because of progressive disease; the 27 patients evaluable for response at the end of consolidation achieved a clinical response (63% complete response and 26% partial response). A significant CD4+ and CD56+ depletion was observed after induction and during consolidation therapy; two herpes zoster virus infections and one perianal abscess represented major infectious morbidities registered during the study. Based on our preliminary data, the combination of chlorambucil with rituximab seemed to be well tolerated and active. Its definitive role in the treatment of low-grade NHL should be further evaluated in randomized trials.

Peg-filgrastim (PEG-FIL), a polyethylene glycol-conjugated form of granulocyte colony-stimulating factor (G-CSF), has been introduced in clinical practice and is effective in shortening the time of neutropenia after cytotoxic chemotherapy. G-CSF has emerged as the preferred cytokine for hematopoietic progenitor cells' (HPC) mobilization. Nevertheless, data on the ability of PEG-FIL in this field have been published.We review publications in the field with the goal of providing an overview of this approach.PEG-FIL may be able to mobilize CD34(+) cells in a more timely fashion than G-CSF, with the advantages of only a single-dose administration, an earlier start and a reduction in the number of apheresis procedures. The main controversies concern the dosage of the drug and the optimal dose. In the context of chemo-mobilization, a single dose of 6 mg PEG-FIL seems effective in terms of HPC's mobilization and there is no increase in this effect if the dose is doubled to 12 mg. Steady-state mobilization requires higher doses of PEG-FIL and this approach is not cost-effective when compared with G-CSF. The experiences with PEG-FIL in the healthy donor setting are very limited.

Fludarabine (FLUDA) based chemotherapy has shown promise in both initial and salvage treatment of low-grade non Hodgkin's lymphomas (LG-NHL). Recently, more aggressive therapies followed by autologous hemopoietic progenitor cell rescue, have also been successfully employed in these patients. However, this procedure, due to several factors including previous therapeutic regimens, is often limited by an inadequate collection of peripheral blood stem cell (PBSC). At present, very little data is available on the effect of FLUDA containing regimens in PBSC collection. We report our preliminary experience showing a possible correlation between FLUDA based chemotherapy regimens employed before mobilization and inability to collect an adequate number of blood derived hematopoietic progenitors for autologous PBSC transplantation in LG-NHL patients.

After primary infection in early life, human herpesvirus 6 (HHV-6) remains latent in the body and may reactivate in subjects with poor immune status. A 180-day longitudinal study of HHV-6 infection was carried out in 23 autologous bone marrow transplant recipients to evaluate reactivation of HHV-6; two of these patients underwent a double transplant. The patients were monitored prospectively for HHV-6 DNA in peripheral blood mononuclear cells (PBMC) by hot start nested PCR. Positive samples were typed by the enzymatic restriction protocol. Positive plasma samples were also tested for HHV-6 DNA. Antibodies against HHV-6 were measured by immunofluorescence. Five and two out of 23 patients had intermittent and persistent positivity to HHV-6 DNA in PBMCs, respectively; four patients carried variant B, and the other three patients both A and B. None of the respective plasma samples were positive. Two patients were positive for HHV-6 antibodies. Since the significance of HHV-6 DNA in PBMCs is unclear, these findings do not necessarily indicate active infection but may be due to mild immunosuppression in autologous BMT recipients.

Infectious complications still represent a major problem in patients submitted to bone marrow transplant (BMT); approximately 40% of febrile episodes are associated with infection and one-third of these are bacteremias. Opinions about the best appropriate empiric regimens are based on evaluation of cost, potential for adverse side-effects, development of bacterial resistance, prevalent nosocomial infections. In order to assess the clinical and microbiological effectiveness of an aggressive approach, we performed a prospective open study in 72 neutropenic febrile BMT patients, employing a triple antibiotic association including amikacin 500 mg x 8h, ceftazidime 2 g x 8 h, vancomycin 500 mg x 8 h as first-line empiric treatment. For the purpose of this study, a lasting return of temperature to normal and complete disappearance of either clinical or bacteriological signs of infection without any modification of therapy was considered as success; the persistence of fever after 72 hours or a protocol change was considered as failure. Eighty episodes were enrolled during the course of the study; bacteriological evidence of infection was obtained in 23 (28.7%) febrile episodes. Median duration of antibiotic administration and of febrile episodes were 5 and 2 days respectively. Overall response rate based on clinical responses was 87% and 91% in microbiological documented infections. Death due to sepsis nor toxicity were observed. This triple antibiotic combination appears to be a very effective regimen for the empiric treatment of febrile episodes in severely neutropenic BMT recipients.

Thirty-eight second allogeneic bone marrow transplants (BMT) for acute leukemia relapsed after first BMT were performed in 13 Italian centers between 1987 and 1994. Twenty-one patients had acute myelogenous leukemia (AML), 17 acute lymphoblastic leukemia (ALL); at second BMT 24 patients were in complete remission (CR) and 14 in relapse. The median time to relapse after first BMT was 10 months (range 1-70). Grade II or greater acute graft-versus-host disease (GVHD) after second transplant occurred in 34.2% of patients and a chronic GVHD in 31.5% of patients. Twenty-four patients died: seven from early transplant-related mortality (TRM), 13 from relapse and four from late toxicity. As of 31 July 1996, at a median follow-up of 47 months (range 22-85), there are 14 survivors. The three-year probability of TRM, relapse and event-free survival (EFS) is 28%, 40% and 42% respectively. In 20 of 27 evaluable patients, remission duration after second BMT was longer than after the first BMT. A diagnosis of AML was correlated with a better outcome. These data support the usefulness of second allograft in selected patients with AML relapsing after a first BMT.

Background Although the efficacy of plerixafor in peripheral blood stem cell (PBSC) mobilization has been explored in several studies, factors associated with successful plerixafor mobilization after administration of granulocyte–colony-stimulating factor (G-CSF), with or without chemotherapy, have not been investigated. We analyzed data on PBSC mobilization from a large Italian database of lymphoma and myeloma plerixafor-treated patients. Study Design and Methods Two endpoints were established to define successful mobilization: patients with at least 2 × 106 CD34+ cells/kg collected by three leukapheresis procedures and patients achieving a peak count of at least 20 × 106 CD34+ cells/L during mobilization. Results Plerixafor achieved successful mobilization in both predicted (n = 64) and proven poor mobilizers (PMs; n = 143), classified according to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) criteria. Successful mobilization was independent of type of mobilization (steady state or chemotherapy); age; sex; disease; number or type of chemotherapy regimens preceding plerixafor; radiation therapy; prior treatment with melphalan, carmustine, lenalidomide, and radioimmune conjugates; and laboratory variables. Multivariate analysis identified previous fludarabine treatment and premobilization platelet count as predictors of successful mobilization. Conclusion This large, prospective, nationwide study confirmed plerixafor efficacy for mobilizing PBSCs when added to G-CSF with or without chemotherapy. Plerixafor can overcome negative effects of most predictors of poor mobilization to achieve satisfactory harvest both in predicted and proven PM.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapeutic option for many malignant and nonmalignant hematologic disorders. Despite this, several factors unfavorably affect the outcome of this procedure and in particular chronic graft-versus-host disease (cGVHD) remains the principal cause of morbidity after allogeneic transplantation. Here we present our experience regarding a patient affected by extensive chronic GVHD (cGVHD) treated only with extracorporeal photopheresis procedure (ECP) as first line treatment. The patient, presenting an high risk myelodysplastic syndrome (MDS), underwent an allogeneic peripheral stem cells transplantation. About 2 months after transplantation she experienced a hematological and clinical relapse of MDS. After reinduction therapy with azacitidine she obtained a second complete remission. Because of the risk of relapse related to a strong immunosuppressant therapy and the previous infectious complication, we decided to start a treatment with ECP alone for cGVHD. After six procedure the patient obtained a complete resolution of all signs and symptoms of the cGVHD. This experience may support the possibility to use only an immunomodulant treatment like ECP for the cGVHD, reducing the risk of complications of prolonged immunosuppressant treatment.

With the aim to assess the efficacy of subcutaneous cladribine in combination with rituximab, 29 newly diagnosed/pretreated WM patients were enrolled in a multicenter phase II trial. Intended therapy consisted of rituximab on day 1 followed by s.c. cladribine 0.1 mg/kg for 5 consecutive days, administered monthly for 4 cycles. The expression of genes involved in cladribine metabolism was evaluated. With a median follow-up of 50 months the ORR rate observed was 89.6% without any difference between newly or pretreated patients (P=.522). The therapy was well tolerated; no major infections were observed, no patients developed transformation to high-grade NHL nor myelodysplasia. Low expression levels of hCNT1 correlated with the failure to achieve a CR (P=.024). The combination of rituximab/cladribine is safe and effective in WM patients requiring treatment. The pharmacogenomic analysis suggests that hCNT1 might be beneficial in predicting clinical response to such a combination treatment.

Plerixafor has been previously reported to improve PBSC collection in pts undergoing PBSC mobilization. Aim of the study was to assess the efficacy of plerixafor and G-CSF in pts with lymphoma who failed previous attempts of PBSC mobilization with conventional schemes of chemotherapy + G-CSF. 35 heavily pre-treated lymphoma pts (29 NHL, 6 HL) classified as “poor mobilizers” were enrolled in a program of compassionate use of plerixafor in 7 Italian centres of REL (Rete Ematologica Lombarda). Median number of previous lines of therapy was 3 and median number of previous attempts of mobilizations was 2. The median number of circulating CD34+ cells/μL following plerixafor was 11/μL. It was ≥10/μL in 17 pts and ≥20/μL in 10 pts; 13 were able to collect ≥2 × 10 6 CD34+ cells/kg with a median of 1 apheresis procedure; 4 pts collected ≥4 × 10 6 CD34+ cells/kg. A total of 6 pts had proceeded to transplant at the time of analysis. The median dose of PBSCs infused was 4 × 10 6 /kg and hematopoietic recovery was regular. In conclusion, plerixafor combined with G-CSF allows a collection of adequate number of PBSC in approximately 40% of cases of poor mobilizer, heavily pre-treated pts with lymphoma, who need consolidation with ASCT.

The aim of this study was to investigate the efficacy of combined treatment with rituximab and subcutaneous cladribine in patients with newly diagnosed and relapsed chronic lymphocytic leukemia (CLL). Forty-three patients with active CLL or small lymphocytic lymphoma received rituximab 375 mg/m(2) on day 1 and cladribine 0.1 mg/kg subcutaneously on days 2-6. The treatment was repeated every 4 weeks for a total of four cycles. Sixteen patients were pretreated. The overall response rate was 88% (50% complete remission and 38% partial remission). The median time to treatment failure was 37.9 months. Grade 4 neutropenia developed in 5% of patients. The data indicate that combination therapy with rituximab and cladribine is a valuable and safe treatment for patients with CLL.

VAD, (Vincristine, Doxorubicin and Dexamethasone) was initially proposed as a salvage therapy for myeloma patients in whom prior alkylating agent therapy failed, although in recent years VAD has been surpassed by novel combination therapies with new biological agents such as thalidomide (and its derivative, lenalidomide) and bortezomib. After the excellent results obtained by the novel agents, VAD can no longer be proposed in preparation to autologous transplantation, although there are still indications that VAD remains useful and clinically relevant in the initial treatment of symptomatic multiple myeloma.