ALBERT

Description: In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclo-phosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemo-therapy as a first-line treatment for high-risk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P 〈 .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P 〈 .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P 〈 .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; (2) R-HDS ensures superior disease control and molecular outcome than CHOP-R, but no OS improvement; and (3) CHOP-R failures have a good outcome after salvage R-HDS, suggesting that relapsed/refractory FL could be the most appropriate setting for R-HDS–like treatments. This trial was registered at www.clinicaltrials.gov as no. NCT00435955.

Description: Abstract 1658 Poster Board I-684 Introduction NHL patients with refractory disease or relapsing after autologous or allogeneic stem cell transplant (SCT) have very poor prognosis with currently available salvage chemotherapy. Sorafenib (Nexavar, BAY43-9006, Bayer) is an oral multikinase inhibitor approved by FDA for the treatment of renal cell carcinoma and hepatocellular carcinoma. Sorafenib exerts a broad range of antiproliferative, antiangiogenic, and proapoptotic effects against a variety of nonhematological tumors through the inhibition of the RAF/MEK/ERK pathway, the receptor tyrosine kinases c-kit, Flt3, RET, as well as the proangiogenic vascular endothelial growth factor receptors (VEGFRs), and platelet-derived growth factor receptor-β (PDGFR-β). Several lines of evidence suggest that Sorafenib might have a significant clinical impact in the treatment of malignant lymphomas by overcoming the cytoprotective effects of Bcl-XL, ERK, and Mcl-1 and eventually targeting additional signalling pathways relevant to lymphomagenesis. Our preclinical data demonstrating a marked cytotoxic activity of Sorafenib against NHL cell lines in vitro and in vivo in xenograft models, established the rationale for this currently ongoing phase II study aimed to determine safety and activity of Sorafenib in relapsed/refractory NHL. Methods Between March 2008 and May 2009, 21 patients (16 males and 5 females; median age, 65 years; range, 29-74 years) with relapsed/refractory diffuse large B cell lymphoma (DLBCL, n = 11), follicular lymphoma (FL, n =4), mantle cell lymphoma (MCL, n =2), lymphoplasmacitoid lymphoma (LPL, n =1), chronic lymphocytic leukemia (CLL, n =2), and peripheral T-cell lymphoma (PTCL, n =1) who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled in this phase II trial. Prior to study entry, patients received a median of 4 (range 2 - 7) lines of treatment, including autologous SCT in 15 (71%) and an additional allogeneic SCT in 5 (24%) cases. At study entry, 7 (33%) patients had relapsed and 14 (67%) refractory disease. Eligibility criteria included absence of any available treatment options of proven efficacy, at least one target lesion ≥2 cm, ECOG performance status of 0-1, and adequate bone marrow, liver and renal functions. Sorafenib (400 mg BID, per os) was administered continuously until disease progression or appearance of clinical significant toxicity probably related to study drug. Tumor responses were assessed according to the revised response criteria for malignant lymphoma of the International Working Group. NCI CTCAE v3.0 was used for toxicity assessment. Results To date, 21 patients received a median of 3 months (range, 1 – 11) of Sorafenib therapy. All patients are evaluable for toxicity and response, and 1 patient is still on therapy. Overall, therapy was well tolerated without significant adverse events. The most common drug-related non-hematological toxicities were grade 1-2 mucositis (14%), diarrhea (24%), hand-foot syndrome (24%), anorexia (29%), and fatigue (29%). Grade 3-4 hand-foot syndrome occurred in 19% of patients. Hematological toxicities included grade 1-2 neutropenia (10%) and thrombocytopenia (24%). Grade 3-4 neutropenia and thrombocytopenia were observed in 14%, and 24% of patients, respectively. Best response to Sorafenib included 1 (5%) complete remission (CR) occurring in the patient with LPL, and 1 (5%) partial remission (PR) in a patient with cutaneous DLBCL, for an overall response rate (ORR) of 10%. In both patients, response duration was 6 months. In addition, 9 (42%) patients achieved stable disease (SD) for a median of 3 months (range, 2 – 10), with 3 (14%) patients achieving SD for ≥6 months, while 10 (48%) patients progressed. Upon Sorafenib treatment, an extensive necrosis involving the central area of the tumor associated with a nearly complete disappearance of tumor vascularization was documented by computed tomography and contrast-enhanced ultrasound in two DLBCL and one FL patients bearing latero-cervical or abdominal lymphoid masses. Conclusions Sorafenib as a single agent was well tolerated. Despite limited clinical activity (10% ORR), disease stabilization was experienced by 42% of patients. The potent antiangiogenic activity of Sorafenib in NHL patients bearing highly vascularized lymphoid masses suggests that further research should focus on combinations of Sorafenib with molecularly targeted agents eventually exerting antivascular activities. Disclosures Off Label Use: The multikinase inhibitor Sorafenib has been used in a phase II trial in patients with relapsed/refractory NHL.

Description: Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p 〈 0.001) and thrombocytopenia (31.4% vs 2.6%, p 〈 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

Description: Abstract 3310 Poster Board III-198 Lymphoma patients relapsing after allogeneic stem cell transplantation (alloSCT) have a dismal prognosis. Relapsed disease is often chemorefractory and few therapeutic options are available. Few reports have assessed the efficacy of donor lymphocyte infusions (DLI) for relapse treatment. We conducted a retrospective study to assess whether DLI may improve survival outcomes of relapsed patients as compared to salvage chemotherapy, and to explore the potential benefit of Rituximab as salvage treatment. We collected data of 146 consecutive patients with Hodgkin's (HL) and non-Hodgkin's (NHL) lymphoma allografted with reduced intensity conditioning in 2 Italian hematologic centres between 1999 and 2007. Patients relapsed after alloSCT were the target population of our study, and their treatment and survival outcomes were analyzed. Progression free (PFS) and overall survival (OS) were defined as the time from first to second relapse or death and the time from first relapse to death, and were analyzed by Kaplan-Meier method and log-rank test. Relapse incidence (RI) was defined as the time from first to second relapse considering non-relapse mortality as competing event, and it was analyzed by Cumulative Incidence method and Gray's test. Multivariate analysis was done with Cox method. Fifty-seven (39%) of all 146 patients relapsed at a median of 545 days, 48 of them (84%) were treated for relapse, 9 (16%) were not treated due to early death for progression (6) or infection (2) or response to cyclosporine withdrawal (1). Treated patients had a median age of 50 years (range 19-65), 18 (38%) were female, 12 (25%) had HL, 13 (27%) indolent and 23 (48%) aggressive NHL. Previous lines of chemotherapy were 3 (range 2-7). Twenty-four (50%) patients had undergone an autologous transplant (autoSCT). All patients were allografted from siblings (32, 67%) or from matched unrelated donors (16, 33%). Twenty-four (50%) had 〉1 comorbidity Sorror score at transplant. Twenty-four (50%) patients received DLI alone or with chemotherapy for relapse treatment, 24 (50%) received chemotherapy alone. Median DLI administered were 2 (range 1-5) with a median of 1×10 7CD3+ per DLI. Ten patients (21%) could not receive DLI because of GVHD (5), progressive disease (3), infection (1), donor's loss of eligibility (1). Seventeen patients (35%) were treated with Rituximab alone or combined with chemotherapy, 10 (21%) received both DLI and Rituximab. One- and 2- years OS (median 720 days) and PFS (median 269 days) were 61% and 50%, 39% and 30%, respectively. One- and 2-years RI were 45% and 65%. Age, sex, pre-transplant disease status, therapy lines, comorbidities, donor type, autoSCT did not influence OS nor PFS or RI. Patients with aggressive NHL had a worse PFS (p=0.01), a higher RI (p=0.01) and a trend to reduced OS (p=0.05). Patients treated with DLI had a better PFS than patients treated with salvage chemotherapy alone (1-year PFS 54% with DLI vs 24% without, p=0.005), a significantly reduced RI (1-year RI 38% with DLI vs 67% without, p=0.007), and a trend towards a better OS (1-year OS 79% with DLI vs 38% without, p=0.06). Rituximab treatment improved OS (1-year OS 82% with Rituximab, 50% without, p=0.009) but did not significantly impact PFS or RI. As compared to chemotherapy alone, patients treated with both DLI and Rituximab had better PFS (1-year PFS 60% vs 37%, p=0.04) and OS (1-year OS 90% vs 50%, p=0.006) and a trend to reduced RI (1-year 30% vs 58%, p=0.05). The multivariate analysis considered as covariates disease (HL vs indolent NHL vs aggressive NHL), age (

Description: Background. Recent reports have shown that Rituximab added to conventional chemotherapy may significantly improve the prognosis of CD20-positive Diffuse Large B-cell Lymphoma (DLB-CL). However, patients with unfavorable clinical presentation still have a poor outcome. Other studies have documented an increased anti-lymphoma activity upon addition of Rituximab to intensified treatments with autologous peripheral blood stem cell (PBSC) transplantation. Based on these premises, a prospective multicenter study has been performed on the use of a Rituximab-supplemented high-dose sequential (R-HDS) chemotherapy schedule with PBPC autografting in patients with unfavorable DLB-CL, defined as score 2 and 3 (intermediate-high or high) according to the age-adjusted International Prognostic Index (aaIPI). Methods. The R-HDS regimen included: (i) an initial debulkying with 3 APO courses; (ii) a high-dose (hd) phase consisting in the sequential administration, at 15–20 day intervals, of hd- cyclophosphamide (7gr/sqm, with two Rituximab doses at 375 mg/sqm), hd-Ara-C (2gr/sqm b.i.d. for 6 days with Rituximab), and hd etoposide + Cisplatin; (iii) a final myeloablative phase (hd-Mitoxantrone + L-Pam) with PBSC autografting and 2 more doses of Rituximab. Involved-field radiotherapy was scheduled on areas of previous bulky disease or residual lesions. Six Centers affiliated to the GITIL group (Gruppo Italiano Terapie Innovative nei Linfomi) participated in the multicenter study. Patient enrollment started in November 1999 and was closed in September 2004. Results. Overall, 112 previously untreated patients aged ≤ 60 years, with CD20-positive DLB-CL and aaIPI score 2 (74 pts) or 3 (38 pts), entered the study protocol and are evaluable. There were 5 early toxic deaths (3 sepsis in the hd-phase, 1 pneumonia and 1 leucoencephalopathy from JC-virus infection after autografting) and one late toxic death due to pneumonia which occurred at 10 mos. after R-HDS. The TRM was 5.3%. Ninety patients (80 %) achieved Complete Remission (CR). At a median follow-up of 24 mos, 90 patients (80%) are alive and 83 (74%) are in continuous CR (CCR), leading to a 5.3-yr event-free survival (EFS) projection of 71%. There was a trend towards a better outcome in aaIPI 2 vs. 3, although the difference was not statistically significant. Conclusions. The CR, OS and EFS rates observed after R-HDS compare favorably with the poor outcome anticipated in aaIPI 2–3 patients managed with conventional chemotherapy. The results of this phase II study prompted an ongoing phase III GITIL multicenter study to compare R-CHOP vs. R-HDS in younger patients with high-risk DLB-CL.

Description: Background: New agents have been introduced as induction prior to autologous stem cell transplant (ASCT) and as consolidation/maintenance thereafter to improve complete response (CR) rates. In this trial we evaluate Bortezomib plus Pegylated-lyposomal-doxorubicin and Dexamethasone (PAD) as induction therapy prior to reduced intensity ASCT, followed by consolidation with Lenalidomide and Prednisone (LP) and maintenance with Lenalidomide alone (L). Methods: Newly diagnosed multiple myeloma (MM) patients aged 65–75 years were eligible. Induction regimen consisted of 4 21-day PAD cycles (Bortezomib 1.3 mg/m2 days 1, 4, 8, 11, Pegylated-lyposomal-doxorubicin 30 mg/m2 day 4 and Dexamethasone 40 mg days 1–4, 8–11, 15–18). Two cycles of Cyclophosphamide 3 g/m2 plus Granulocyte-Colony Stimulating Factor were used to harvest stem cells. Patients were conditioned with tandem Melphalan 100 mg/m2 (MEL100) followed by stem cell support. After ASCT patients received consolidation with 4 28-day LP cycles (Lenalidomide 25 mg days 1–21 plus, Prednisone 50 mg every other day) followed by Lenalidomide alone maintenance (10 mg days 1–21 every 28 day). Primary objectives were safety (grade 3 non-hematologic toxicity 〈 30%) and efficacy (near CR rate 〉 35%). Results: One-hundred and two patients have been enrolled. After PAD cycles at least partial response (PR) rate was 94%, at least very good partial response (VGPR) was 59% including 13% CR. After tandem MEL100, 88% of patients achieved at least VGPR and 41% CR. After LP consolidation all patients obtained PR, 88% at least VGPR and 53% immunofixation negative CR. After a median follow-up of 14 months, 1-year progression free survival (PFS) was 92%, 1 year time to progression was 97% and 1 year overall survival was 92%. PFS was not significantly affected β2-microglobulin levels (p=0.10), presence of chromosome 13 deletion (p=0.5) or t(4;14) (p=0.61). During PAD, grade 3–4 adverse events included thrombocitopenia (13%), neutropenia (11%), infections (18%), gastrointestinal toxicities (12%), peripheral neuropathy (11%) and deep vein thrombosis (6%). During LP consolidation, grade 3–4 toxicities included neutropenia (18%), thrombocytopenia (6%), infections (6%) and deep vein thrombosis (6%). The other grade 3–4 toxicities occurred in less than 5% of patients. Conclusions: Bortezomib as induction regimen prior to reduced intensity ASCT, followed by Lenalidomide as consolidation maintenance is a highly effective regimen in elderly patients. Updated results will be presented at the meeting.

Description: Several groups have reported the results of Allo-SCT following a RIC regimen in relapsed and refractory lymphomas. However, the long-term efficacy of this strategy is still unknown. We report herein the results of a prospective multicenter phase II trial at median follow-up of 5 years. A total of 194 relapsed/refractory lymphomas received the same RIC regimen (thiotepa, cyclophosphamide and fludarabine) followed by Allo-SCT from sibling donors. Histologies were non-Hodgkin’s lymphomas (NHL) [indolent (LG-NHL, n=68), including follicular lymphoma (FL, n=29), chronic lymphocytic leukemia (CLL, n=35), other (n=4); aggressive (HG-NHL, n=87), including B-cell phenotype (n=43), T-cell phenotype (n=28), mantle cell lymphoma (MCL, n=16)] and Hodgkin’s lymphoma (HL, n=39). 133 (68%) of 194 patients (pts) had chemosensitive disease and 100 (52%) of 194 failed a previous autologous transplantation. Median follow-up was 60 months (range, 15–113). At last follow-up, 116 pts are alive (59%) and 78 died from any cause [n=47 for disease progression, n= 30 for non-relapse mortality (NRM), n=1 not assessable]. The 5-year overall survival (OS) and progression-free survival (PFS) were 62% and 70% for LG-NHL, 61% and 59% for HG-NHL, and 42% and 19% for HL, respectively. The median time to relapse was 7 (range, 2–30), 4.5 (range, 1.6–33), and 5.5 (range, 0.4–42) months for LG-NHL, HG-NHL, and HL respectively. Pts with chemosensitive disease at Allo-SCT had 5-year OS and PFS of 69% and 61%, while those with refractory disease had 5-year OS and PFS of 35% and 45%, respectively. Status of disease at Allo-SCT influenced significantly long-term outcome in HG-NHL and HL [chemosensitive versus chemorefractory: 73% versus 32% (p

Description: Background: Telomeres are linear DNA structures located at the ends of chromosomes which undergo progressive shortening in somatic tissues with high replicative rate, including hematopoietic cells. Due to this peculiarity, telomere length (TL) has been used as a marker of cell senescence and of previous replicative stress. Following hematopoietic stem cell transplant (SCT) a variable shortening of TL has observed, this variability has been in part ascribed to differences in post-graft replicative stress. In a recent report (Ricca I et al, Leukemia 2005), we have analysed TL on peripheral blood progenitor cell (PBPC) harvested after 2 tightly-spaced hd-chemotherapy courses, i.e. hd-Cyclophosphamide (CY) and hd-Ara-C and found that TL of PBPC was markedly shortened at the second hd-course. Aim of this study was to investigate how TL of grafted cells may influence telomere status of post-SCT hematopoietic cells in both the autologous and allogeneic setting. Patients and Methods: TL was monitored in 20 patients undergoing autograft with PBPC collected after hd-CY (10 patients) or hd-Ara-C (10 patients) and in 10 patients undergoing allograft with PBPC mobilized from healthy donors. Overall, patient median age was 48 years (range 19–64). The amount of CD34+ cells grafted was 7 × 106 CD34+/Kg (range 2,03–22,6). TL was assessed both on the graft and on Bone Marrow (BM) samples taken at a median time of 14 months (range 12–17) after SCT. All patients were in continuous complete remission at the time of TL analisis. TL was evaluated by Southern blot, as previously described (Rocci A et al, Exp Hematol 2007). Results: As expected, TL was found markedly shortened in post-Ara-C, with median TL of 8051 bp (range 5209–11024 bp) and 7066 bp (range 4800–8906 bp) in PBPC post-CY and post-Ara-C, respectively (p

Description: Introduction. High-dose (hd) therapy with stem cell autograft is an effective treatment for both non-Hodgkins (NHL) and Hodgkins Lymphoma (HL). However, the occurrence of secondary myelodysplastic syndrome/acute leukemia (sMDS/AL) is a critical issue, representing a major cause of failure in patients potentially cured after hd-therapy. Aim of the study. To evaluate incidence and risk factors of sMDS/AL in a large series of lymphoma patients, treated with the hd-sequential (HDS) chemotherapy approach, followed by peripheral blood progenitor cell (PBPC) autograft. Patients and Methods. Data have been collected on 1,347 lymphoma patients treated in the last two decades at 11 Centers, associated to GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). The series included 234 HL and 1,110 NHL (276 low-grade); median age was 46 yrs; 771 were male; 640 (47.5%) patients received HDS front-line, 707 as salvage treatment. All patients received either the original or the modified HDS regimen: 152 (13%) patients were unable to complete the program with autograft; among 1,171 autografted patients, only 79 received a TBI-conditioning regimen. Nearly all patients (97%) were autografted with PBPC (median CD34+ cells: 8 × 106/kg), only a few received BM cells; PBPC were usually collected after hd-cyclophosphamide, or, in a subgroup (28%), after a 2nd round of mobilization, with hd-Ara-C; there were no significant differences in the amount of infused cells between PBPC of the 1st vs. the 2nd mobilization course. HDS was supplemented with Rituximab in 525 (39%) patients. Results. At a median follow-up of 5.5 yrs, Overall Survival projections at 5 and 10 yrs are, respectively, 62% and 54% for the whole series, 69% and 61% for patients treated at diagnosis. Overall, 46 (3.4%) patients developed s-MDS/AL, with a cumulative incidence of sMDS/AL of 3.2%, 4.7% and 8.4% at 5, 10 and 20 yrs, respectively. Median time of s-MDS/AL occurrence was 35 months since autograft. In competing risk univariate analysis, a few clinical parameters, including age 〉 45 yrs, male sex, advanced stage, Rituximab administration, autograft with PBPC of 2nd round of mobilization, displayed a variable increase in the cumulative incidence of sMDS/AL; however, on multivariate analysis, only male gender and reinfusion of PBPC of the 2nd mobilization course were associated with sMDS/AL occurrence (SDHR: 2.93, p=0.007 for male gender; 2.54, p=0.004 for graft with PBPC collected at the 2nd round). Conclusions. Overall incidence of sMDS/AL in HDS-treated patients is analogous to that reported in other recent surveys on lymphoma patients treated with hd-therapy and autograft, with a higher risk recorded among males; furthermore, the study suggests that the quality of CD34+ve cells employed for autograft may be critical for the post-graft development of sMDS/AL.

Description: Osteonecrosis of the jaw (ONJ) is a frequent complication in bisphosphonate-treated multiple myeloma (MM) patients. The pathogenesis is unclear, and major risk factors are duration of bisphosphonate treatment and dental procedures. The histology of osteonecrotic bone shows osteomyelitis and inflammatory infiltrates, and, in most cases, presence of Actynomycetes. Since dental procedures are a major risk factor for ONJ development and oral microflora can be involved in the pathogenesis of the disease, we conducted a retrospective observational trial comparing ONJ occurrence and related risk factors in two groups of MM patients, who received zoledronic acid treatment at two Italian hematological centres. In one centre all patients systematically received as antibiotic prophylaxis amoxicillin-clavulanate 1 gm bid or levofloxacin 500 mg once a day starting from one day before to 3 days after any dental procedure (group A, 52 patients), while in the other centre patients did not receive any prophylaxis (group B, 61 patients). Dental procedures were categorized according to their invasivity and their supposed probability to cause ONJ. Extractions, implants, and professional cleanings were considered at high risk, while fillings were considered low risk procedures. Thirty-three group A patients (63%) and 32 group B patients (52%) received high risk procedures; 4 group A patients (8%) and 5 group B patients (8%) received low risk procedures, while 15 (29%) and 24 (39%) patients, respectively, had a denture. The duration of zoledronic acid exposure differed significantly between the two groups, with a median of 26 months for A patients and 12 months for B patients (p