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Inhibitors in patients with hemophilia are a rare complication of a rare disease causing pain and disability in patients and impairment to the quality of their lives. Recent advances in treatment have brought improvements, but they have done so by absorbing larger amounts of financial resources. This study involved 52 Italian patients with hemophilia with high-responding inhibitors who were longitudinally observed for 18 months to evaluate concomitantly cost of care and quality of life. Overall, 0.6 bleeding episodes per patient per month were recorded. This frequency of events was lower than that reported in other cohorts of patients with hemophilia who were not taking inhibitors. The average monthly cost of care was, in euros, €18 000 (US $18 000) per patient, mainly because of treatment products. Recombinant activated factor VII, mostly used for orthopedic surgery, represented 50% of the expenses. Quality of life, measured through validated questionnaires, was similar to that of patients with severe hemophilia without inhibitors. In particular, physical quality of life was similar to that in patients with diabetes and on dialysis, whereas mental quality of life was comparable to that in the general population. This study shows that hemophilia complicated by inhibitors, a prototype of rare disease, requires high amounts of resources for management that provides a satisfactory quality of life. (Blood. 2003;102:2358-2363) more...

PURPOSE: The HD2000 trial compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) versus the combination of cyclophosphamide, vincristine, procarbazine, prednisone (COPP) with epidoxorubicin, bleomycin, vinblastine (EBV), lomustine, doxorubicin, and vindesine (CAD) (MOPP/EBV/CAD [CEC]) in 305 eligible patients with advanced-stage Hodgkin's lymphoma (HL). The previous analysis with 41 months median follow-up had indicated that BEACOPP was associated with a significantly improved Progression Free Survival (PFS) compared with ABVD, with a predictable higher acute toxicity. At time of previous analysis none of the study arms resulted in a better Overall Survival (OS). We here report analysis of long-term outcome and toxicity. PATIENTS AND METHODS: Three hundred and five eligible patients with stage IIB, III, or IV were randomly assigned to receive six courses of ABVD (n=103), four escalated plus two standard courses of BEACOPP (n=100), or six courses of CEC (n=102), plus a limited radiation therapy program; radiotherapy was administered in 46, 42, and 42 patients in the three arms, respectively. Study enrolment was completed in June 2007. In January 2014 we updated the study follow-up with the aim of providing data on survival and on late events. RESULTS: At time of current analysis the median follow-up was 119 months (range 1-169) with 92% of patients with a last contact later than January 2012. In the prolonged observation period 23 additional failures (cumulative=82)were recorded, including 17 new relapses/progression (cum=71) and 6 deaths not related to lymphoma progression (cum=11). Additional relapses and progressions were observed in 5, 7 and 5 patients treated with ABVD (cum=31), BEACOPP (cum=17), and CEC (cum=23), respectively. No death unrelatedto lymphoma progression was recorded among patients treated with ABVD, while 8 (+4) and 3 (+2) events were documented among patients treated with BEACOPP or CEC, respectively. The 10-year PFS was 69%, 74% and 74% in the ABVD, BEACOPP and CEC arm, respectively (P=0.639). Using ABVD as reference, Hazard Ratio for PFS for BEACOPP and CEC was 0.73 (CI95% 0.43-1.25) and 0.80 (0.47-1.36); this result was adjusted by IPS. Overall 42 patients died (+19), 13 (+5) in the ABVD arm, 15 (+7) in the BEACOPP arm and 14 (+7) in the CEC arm. The 10-year overall survival rates were 84%, 84% and 86% for ABVD, BEACOPP and CEC, respectively (P =0.883). A total of 11 second malignancies were documented including 2 MDS/AML (1 BEACOPP and 1 CEC), 2 non-Hodgkin’s Lymphoma (1 BEACOPP and 1 CEC), and 7 solid cancers: 2 lung cancer (BEACOPP), 2 bladder cancer (2 CEC), 1 sarcoma (BEACOPP), 1 Kaposi sarcoma (BEACOPP) and 1 thyroid cancer (ABVD). The risk of second malignancy at 10-year was 6.7, 4.4 and 0.9 for BEACOPP, CEC and ABVD, respectively; the difference between BEACOPP and ABVD was statistically significant (P=0.027). CONCLUSION : With the updated follow-up of the HD2000 trial we confirm that patients with advanced HL have similar high chances of survival when treated with ABVD, BEACOPP or CEC. With this long-term analysis we were not able to confirm the previously observed superiority of BEACOPP over ABVD in terms of PFS mainly due to a higher rate of secondary malignancies observed after BEACOPP. Disclosures No relevant conflicts of interest to declare. more...

Cytomegalovirus (CMV) is an important cause of morbidity and mortality in patients who have undergone severe immunosuppressive therapy. Ganciclovir continues to be the first choice for pre-emptive therapy, but it needs multiple intravenous daily administration for three weeks and may cause myelosuppression. Cidofovir is a non myelotoxic nucleotide analogue effective against CMV; its favourable pharmacokinetic profile allows a once-a-week dosing. We reviewed a database on 110 consecutive Autologous Stem Cell Transplant (ASCT) and that of 15 Chronic Lymphocytic Leukemia (CLL) patients treated with alemtuzumab. All patients were virologically monitored by quantification of pp65 antigenemia in peripheral blood. Cytomegalovirus infections were identified respectively, in 13 of 110 (12%) ASCT group and in 10 of 15 (66%) CLL group. Nine out 23 CMV reactivation showed manifestation of the infection. All patients were treated on outpatient basis. Patients with a positive pp65 assay were treated with cidofovir 5 mg/kg once-a-week for two weeks followed by one or two doses every two weeks. Twenty-three patients (13 autologus, 10 alemtuzumab) had 23 episodes of CMV-pp65 detection treated with cidofovir. The first positive antigenemia occurred after a median of 36 days from starting treatment (range 5–20) and the median antigenemia level at first appearance was 2 (range 1– 89). The treatment produced regression of symptoms in all cases and clearance of the virus in 21 (11 post-transplant 84%; 10 post alemtuzumab 100%), stained by CMV antigenemia. Median duration of therapy was 21 days (range 14–30 days) and the time to the first undetectable antigenemia was seven days (range7–28). We did not observe any further CMV reactivations, also in six of the ten patients who restarted treatment with alemtuzumab after the end of pre-emptive therapy. We did not observe any of the side effects potentially related to cidofovir administration: notably, none of the patients experienced renal toxicity, proteinuria, nausea or vomiting, ophthalmological or neurological toxicity. In our experience, pre-emptive therapy of CMV infection with cidofovir is safe and effective. In our opinion it could be considered an interesting alternative to ganciclovir for pre emptive therapy, particularly advantageous for treatment of CLL and ASCT ambulatory patients at low risk of developing CMV disease. more...

Introduction . BEAM (carmustine, etoposide, aracytin, melphalan) is a conditioning regimen used in autologous hemopoietic stem cell transplantation for Hodgkin Lymphoma and non Hodgkin Lymphoma, with acceptable toxicity and high efficacy. In our study we replaced the carmustine with fotemustine, an analogous chloroethylnitrosourea. Primary end-point was to valuate the feasibility of this modified conditioning regimen. Patients and Methods . 86 patients were consecutively conditioned in seven BM-Units with FEAM before receiving aHSCT. 44 patients (63%) were male, 32 (37%) female. Median age was 51 years (range, 18–77). 23 patients (27%) had HL, 60 (70%) had NHL (2 SLL, 1 LPL, 1 MZL, 2 FL, 6 MCL, 37 DLBCL, 3 BL, 1 B-LBL, 1 T-LBL, 4 u-PTCL, 2 AIL), 1 patient had a B-CLL, 1 a B-ALL FAB L3 and 1 an aggressive NK-cell leukemia. In the lymphoma group, 22 patients (27%) were in stage II (10 with bulky disease), 20 (24%) in stage III and 41 (49%) in stage IV. Among lymphoma patients, 19 (23%) had a bone marrow involvement, 5 (6%) a central nervous system involvement, including 2 primary central nervous system lymphoma. At the time of transplantation, 41 patients (48%) were in CR, 3 (3%) in VGPR, 32 (37%) in PR, 10 (12%) had a resistant-progressive disease (R/PD); 30 patients (35%) were at first line of therapy, 56 (65%) had received more than one line of therapy. Patients received fotemustine 150 mg/m2 on days -7, -6, etoposide 200 mg/m2 and aracytin 400 mg/m2 on day -5, -4, -3, -2, and melphalan 140 mg/m2 on day -1. The median number of CD34+ cells infused was 3.8 × 106/Kg recipient body weight (range, 1–21.8). Results . Only 2 patients were not evaluated for engraftment and toxicity. Among evaluable patients, all engrafted. The median time to neutrophil (N >0.5 × 106/L) and platelet (PLT >20 × 109/L) recovery was 11 (range, 9–19) and 13 days (range, 6–105) respectively. 55 patients (65%) received trasfusions of red blood cell units, with a median of 2 units (range, 1–8). All patients received platelet trasfusions with a median of 2 units (range, 1–15). Toxicity . No chemotherapy-induced nausea and vomiting (CINV) was observed in 17 patients (20%), 53 patients (63%) had CINV grade I–II, 14 patients (17%) grade III, no grade IV was observed. No mucositis was observed in 16 patients (19%), 45 patients (54%) had mucositis grade I–II, 17 patients (20%) grade III, 6 patients (7%) grade IV. No diarrhea was observed in 50 patients (60%), 29 patients (34%) had diarrhea grade I–II, 5 patients (6%) grade III, no grade IV was observed. No epatic toxicity was observed in 80 pts (95%), 1 patient had epatic toxicity grade I, 1 patient grade II and 2 patients grade III, no grade IV was reported. Only one patient had a transient renal toxicity grade II. No pulmonary toxicity was observed. Fever >38, 5°C was documented in 68 patients (81%) with a median duration of 4 days (range 1–25). GRAM-were identified in 15 patients, GRAM+ in 14 patients, yeasts were isolated in 3 patients and there was only one infection by Pneumocystis Carinii. In the other 35 patients (51%) no organism was identified as the source of the fever which was classified as FUO. Outcome . At a median follow-up of 5 months (range, 1–16), 79 patients (92%) are alive. On 75 evaluated patients, fifty-nine (79%) are alive and free from disease. Among the seven deceased patients, three died for PD at day +111, +110 and +75 from transplantation respectively, one died for bacterial meningitis at day +45 from transplantation, after a complete hematologic recovery, one in PR died for gastric haemmorrhage from tumor site, and two (1 CR, 1 VGPR) died for comorbidity, respectively at day +150 and +240 from transplantation. TRM at 100 days was 1%. Among the 75 patients who were evaluated after aHSCT, thirty-five patients, out of thirty-six who were in CR before aHSCT, maintained the CR after, for the other thirty-nine, twenty-seven (69%) achieved the CR (three of these had a CNS involvement before aHSCT), one achieved a VGPR, two a PR (ORR 77%), four had a stable disease and five progressed. Considering as treatment failure the relapse, the progression or the death for any cause, in our study the treatment failure was assessed on 16%. Conclusions . Our study demonstrated the feasibility and the safety of the FEAM, regard its toxicity it was not superior with respect to BEAM. However, a longer follow-up is needed to valuate the efficacy of this modified conditioning regimen in term of clinical response. more...

Radioimmunotherapy (RIT) with 90Y-Zevalin® combined with high dose therapy and autologous stem cell transplantation (ASCT) is gaing increasing importance for the treatment of relapsed or refractory non Hodgkin Lymphoma (nHL). We evaluated the feasibility and the clinical results of the addition of 90Y-Zevalin® at standard dose to BEAM regimen (Z-BEAM) in nHL pts who failed to achieve complete remission (CR) after previous chemoimmunotherapy. Methods. Between October 2005 and June 2008, 53 patients were enrolled in 11 italian centers. The treatment strategy is shown in figure 1. Salvage treatment consisted of 2 courses of R-DHAP. PBSCs were collected after mobilization with DHAP and G-CSF plus in vivo purging with Rituximab. Patients’ characteristics are shown in table 1. Results. The median CD34+ cells infused was 5.5 x10^6/Kilograms (range 2.55–34). All patients engrafted. The median number of red blood cell and platelet transfusion were 4 (1–7) and 6 (1–8), respectively. The median time to platelet and neutrophil counts higher than 20x10^9/L and 0.5x10^9/L were 14 (range, 9–60 days) and 10 days (range, 8–20), respectively. Mucosites occurred in all pts (grade III in 20 and grade IV in 5 patients). Febrile neutropenia occurred in 39 pts (74%). Eight pneumonitis and 12 blood stream infections, mainly by Gram+, were documented. One patient developed an atrial fibrillation. Five pts were not evaluable for response because too early. The 90-day overall response rate was 86% with 74% of CR. Three relapses (relapse rate 9%) and four progression were documented at a median follow-up of 247 days post Z-BEAM (range, 125–818). The potential factor to predict CR was: at last PR before Z-BEAM (p=0.06). Fourthy patients are alive at a median follow-up of 175 days post HST (range, 6–590): thirty pts in CR (57%), three pts in PR (5.5%), three pts in progressive disease (PD, 6%)(fig. 2). Fourtheen pts died (26%): 5 deaths due to TRM before day 90, 1 for ARDS (+230), 1 TRM post a subsequent RIC allotransplant (+95) and 6 due to PD (median follow-up 110 days, range 97–150). The Kaplan-Meyer estimated 3y-EFS is 64%. Five early deaths before day-90 occurred: 2 due to septic shock (day +6 and +39), 1 to pneumonitis (+22), 1 for BK viral encephalites (+61) and 1 to MOF (+14). The Kaplan-Meyer estimated Treatment Related Mortality (TRM) is 9.3%. Two statistically risk factors for 90-day TRM (p Conclusion. In pts with different histology nHL, who failed to achieve CR after previous immuno-chemotherapy, RIT integrated with high-dose chemotherapy (Z-BEAM) is capable to induce 86% of ORR, 74% of CR and 3 ys EFS of 64%, with sustained engraftment and an acceptable extra-haematological toxicity, mainly restricted to pts older then 65 ys. The power of this program needs to be assessed in a larger series of patients and in a randomized fashion. Table 1: Patient Characteristics and 90-day response post HST Figure. 1 Treatment Plan Figure. 1. Treatment Plan more...

Meningeal recurrence in aggressive NHL and ALL occurs in up to 20% of patients and mostly depends on intensity and efficacy of front-line CNS prophylaxis. Liposomal cytarabine (lip araC) is a sustained release formulation of araC with a homogeneous distribution in the neuraxis and a prolonged half life, maintening cytotoxic concentrations in the CSF for more than 14 days. The present study aims to evaluate the safety and tolerability of lip araC in the CNS prophylaxis of NHL and ALL meningeal recurrences. Forty-four patients aged 16–77 years (median 43,9) have been preventively treated with a total of 159 (range: 1–8) doses of lip araC 50 mg. Diagnosis consisted on 33 NHL: 14 high risk-CNS DLBCL (involvement of testes, paranasal sinuses, hard palate, orbit, paravertebral masses and bone marrow or IPI ≥2 with high level of LDH and ≥1 extranodal site involvement), 7 BL, 2 blastoid mantle cell, 7 lymphoblastic, 1 gastric marginal zone lymphoma, 1 anaplastic, 1 follicular, and 11 ALL: 7 B-ALL, 3 T-ALL, 1 hybrid cells. Five patients (1 DLBCL, 1 BL, 2 T-ALL, 1 B-ALL) received lip araC at their 1st systemic recurrence; of them, the DLBCL did not receive previous prophylaxis, instead of the T-ALLs had standard treatment with IT MTX; BL and B-ALL received not specified prophylactic therapy. All patients were treated according to the standard protocols in use for their disease; in particularly, NHL received RCHOP-like treatments, a part of 5 BL (RCODOX-M/R-IVAC-like therapy) and 5 lymphoblastic (hyperC VAD/HD MTX/araC); ALL patients received standard treatments according with GIMEMA, NILG and BMF protocols. Five patients (2 DLBCL, 2 BL and 1 B-ALL) underwent autotransplantation. Four patients received IT or HD systemic MTX during treatment with lip araC. Seven patients received RT, as a part of prophylaxis program. All patients received lip araC 50 mg every 2, 3, 4 or 8 weeks, excepted 2 receiving 30 mg. All patients had corticosteroids for prevention of chemical aracnoiditis. A part of an episode of G2 headache and 18 cases of G1 headache, 8 episodes of G1 nausea/vomiting and 2 cases of localized or diffuse bone pain, no severe toxicity has been noted. So far, after a medium observation period of 9 months (range 1–26) only 1 patient, affected by mantle cell lymphoma, showed CNS recurrence 10 months after diagnosis while in systemic relapse and died. None of the patients developed neurological symptoms or unexpected long term neurological side effects. IT lip araC therapy with concomitant corticosteroids appears to be feasible and well tolerated in the prophylactic setting. Because of only few patients received CNS-directed concomitant therapy, lip araC appears effective towards CNS recurrence in the high risk NHL and ALL. More randomized studies are warranted. more...

Background: Patients with beta Thalassemia Major (TM) require life-long blood transfusions and, to avoid iron overload, Iron Chelation Treatment (ICT), based on 8–12 hour infusions of Deferoxamine (DFO) for 5–7 days/week, and/or Deferiprone (L1) orally administered. ICT regimen often causes low satisfaction and low compliance, with potentially negative consequences on patients’ health, wellbeing and costs. Aims: to investigate direct and indirect costs for TM patients on ICT. Methods: The Italian-THAlassemia-Cost-&-Outcomes-Assessment (ITHACA) was a naturalistic multicentre study conducted to evaluate costs, quality of life, compliance and treatment satisfaction in TM patients undergoing ICT. Patients of any age, on ICT for at least 3 years, were sequentially enrolled at 8 Italian Thalassemia Care Centers. Direct and indirect costs were estimated from retrospective data: those on direct costs were drawn from medical records, referred to a median of 11.6 months before enrolment. As regards as indirect costs, patients completed modified versions of the Health and Labour Questionnaire (HLQ). Questions on indirect costs were referred to a 2 weeks (adults) or a 12 weeks (children) time horizon. Costs were estimated from a societal perspective, using tariffs, prices, average net earning applied in 2006, as appropriate. Results: 137 patients were enrolled and aged a median of 28.3 years (2.7–48.5), 49.6% were male. Overall, mean direct cost was 1,245.33euro/patient/month, with ICT representing 55.4% of costs, followed by transfusions (33.1%), hospitalizations and surgery (3.3%), laboratory and instrumental tests and medical visits (3.1%), concomitant medications (1.6%), non-medical costs (transportation, 3.4%). Patients treated with DFO were 51.5%, 31.6% were treated with L1, 16.9% with DFO+L1. Treatment in patients taking DFO cost on average 552.88euro/patient/month plus 211.20 euro for pump and consumables; patients taking L1 cost 383.25 euro/patient/month, patients taking DFO+L1 cost 918.41 euro. Concerning indirect costs, 116 adults (> 16 years old) completed the HLQ. Sixty-one patients (52.7%) were in paid employment. Twenty-one patients (34.4%) had experienced absenteeism from work in the previous 2 weeks due to ill health. The average absenteeism among patients in paid employment was 0.7 days/week. Indirect costs related to absenteeism were 27.6 euro/patient/week. Fifteen patients (26.6% of patients in paid employment) were hindered by health problems at work. Indirect costs per patient based on hours needed to catch up on tasks neglected due to health problems were 9.4 euro/week. Patients received 1.24 hours of household help/week. Twenty-one children ( Discussion: Transfusions and ICT account for 90% of total costs in TM patients, corresponding to approximately 1,000 euro/patient/month. The disease and the current treatment adopted have a high socio-economic impact on both TM patients and the healthcare system. more...

Background Patients with beta Thalassemia Major (TM) require life-long blood transfusions, which often cause iron overload that may increase patients’ morbidity and mortality. Iron Chelation Treatment (ICT), aimed to reduce iron overload, is based on 8–12 hour infusions of Deferoxamine (DFO) for 5–7 days/week, and/or Deferiprone (L1) orally administered. Current ICT can be related to low satisfaction, low compliance, and potentially negative consequences on clinical effectiveness, patients’ wellbeing and on healthcare costs. Aims: To investigate the Health-Related Quality-of-Life (HRQoL) of TM patients and their satisfaction with ICT. Methods: The Italian-THAlassemia-Cost-&-Outcomes-Assessment (ITHACA) was a naturalistic multicentre study conducted to evaluate costs, HRQoL, compliance and treatment satisfaction in TM patients undergoing ICT for at least 3 years, enrolled at Italian Thalassemia Care Centers. HRQoL was measured in >14 years old patients with 2 generic instruments: EQ-5D; Short Form-36 (SF-36). To measure satisfaction >12 years old patients received a 28-item instrument consisting of 4 domains: ‘perceived effectiveness’, ‘acceptance’, ‘burden’, and ‘side effects’. Each domain scored from from 1 (very dissatisfied) to 5 (very satisfied). Results Based on 126 patients: median age 29.4 years (12.3–48.5), 49.6% male. At enrolment 48.0% were using DFO, 33.6% L1, 18.4% were treated with DFO+L1. 86.5% of patients had at least one TM-related complication, 13.5% changed treatment regimen at least once in a median of 11.6 months before enrolment. With EQ-5D profile patients reported moderate problems with ‘mobility’ (9.1%), ‘self care’ (0.8%), ‘usual activities’ (23.5%), moderate or severe ‘pain/discomfort’ (60.5%) and ‘anxiety/depression’ (39.5%). Mean EQ-5D-Visual Analogue Scale was 73.0 (30–100). The SF-36 Physical Component Summary mean(SD) score was 47.7(8.4), while the mean score estimated in the Italian general population comparable for age and sex is 53.3; the Mental Component Summary mean(SD) score in TM patients was 45.1(8.8), while the Italian general population mean score was 47.7. Mean satisfaction scores were 4.29 (perceived effectiveness), 3.37 (acceptance), 3.87 (burden), and 3.57 (side effects). Simple linear regression analysis showed that satisfaction with burden (r2=12.6%, p Conclusions: TM patients on ICT have impaired levels of physical and mental HRQoL. Therapies improving patients’ satisfaction and compliance to ICT may have positive consequences not only on clinical effectiveness but also on overall patients’ well-being. more...

Hemophilia care results in the absorption of an enormous amount of human and economic resources and it affects patients’ quality of life. The treatment of patients with hemophilia through factor replacement is the result of a complex interaction between patients, physicians and policy-makers, each carrying their individual sets of preferences. The study objective was to establish preferences in adult Italian patients with severe or moderate hemophilia, their physicians and their pharmacists using conjoint analysis. This technique shows how persons are willing to trade between different constituents of health care and thereby estimates their relative importance. This multicenter study involved hemophilia treatment centers in Northern Italy (16) in Central Italy (5), in Southern Italy and islands (11). Patients were consecutively enrolled when meeting the following criteria: age ≥18 years, severe or moderate hemophilia A or B (factor VIII/IX more...