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By real-time quantitative polymerase chain reaction (RQ-PCR), we evaluated BCL2/IgH(+) cells in the bone marrow (BM) and peripheral blood (PB) from 86 patients with follicular lymphoma treated with the sequential administration of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab. At diagnosis, the amount of BCL2/IgH(+) cells in the BM was low (1 BCL2/IgH(+) cell in 1000-100 000 normal cells) in 43% of patients, intermediate (1 in 100-1000) in 34%, and high (> 1 in 100) in 23%. A 2 log decrease of BCL2/IgH(+) cells was achieved after CHOP and an additional 2 log reduction following rituximab. By multivariate analysis, a low level of BCL2/IgH(+) cells in the BM at diagnosis was the best predictor for the achievement of a complete clinical and molecular response. At 5 years, the event-free survival rates of patients with a low/intermediate or high tumor infiltration in the BM were 59% and 32%, respectively. The freedom from recurrence of patients who achieved a molecular response in the BM, no matter whether after CHOP alone or CHOP and rituximab, was 64% as compared to 32% for patients who did not (P < .006). RQ-PCR performed at presentation on BM samples predicts treatment response and long-term clinical outcome in patients with follicular lymphoma.

A retrospective survey of patients with pathologically reviewed extragastric mucosa-associated lymphoma tissue (MALT) lymphomas from 20 institutions was performed. A total of 180 patients with histologically confirmed diagnosis of extragastric MALT lymphomas were studied. Their median age was 59 years (range, 21-92 years). Ann Arbor stage I disease was present in 115 patients (64%) and stage II disease in 16 (9%). Most cases were in the low or low-intermediate risk groups according to the International Prognostic Index (IPI). Forty-one (23%) patients had involvement of more than one extranodal site at diagnosis and in 24 cases (13%) the lymphoma presented at multiple mucosal sites (9 of them with only mucosal involvement, without bone marrow or nodal disease). Lymph node involvement was present in 21%. Patients were treated with a variety of therapeutic strategies, including chemotherapy in 78 cases. The median overall survival (OS) was not reached; the 5-year OS rate was 90% (95% CI, 82%-94%), the 5-year cause-specific survival (CSS) was 94% (95% CI, 87%-97%), and the 5-year progression-free survival (PFS) was 60% (95% CI, 50%-70%). Multivariate analysis showed that Ann Arbor stage was significantly associated with longer OS, nodal involvement with longer CSS, and favorable IPI score with better PFS. At a median follow-up of 3.4 years, 48 patients (27%; 95% CI, 20%-34%) had a relapse, 6 (3%; 95% CI, 1%-7%) showed histologic transformation, and 18 (10%; 95% CI, 6%-15%) experienced the development of a second tumor. Our data confirm the indolent nature of nongastric MALT lymphomas and the high rate of patients presenting with disseminated disease, which, when limited to mucosal sites, was not associated with a poorer outcome.

To the editor: Allogeneic hematopoietic stem cell transplantation (HSCT) can grant long-term control and cure of acute myeloid leukemia (AML) thanks to the antitumor effect of the transplanted immune system. Still, relapse remains an open issue: in the haploidentical setting, we and others

Abstract 743 Background: Acute Graft versus host disease (aGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Conventional treatment with high dose steroids fails to achieve a complete and sustained response in more than 50% of patients. Several second line treatments have been described but none of these can be considered superior or a standard of care (Paul J. Martin et al, BBMT 2012). Among these treatments, the use of third party mesenchymal stromal cells (MSC) has been proposed (LeBlanc et al, Lancet 2008). In this study, we assessed the safety and efficacy of third party human MSC, in a prospective, multicenter, phase I study (EudraCT 2008–007869-23). Methods: Forty-seven patients with steroid-resistant, acute or chronic grade II-IV GvHD were enrolled into this study. Human MSC were obtained from bone marrow harvests of healthy donors and expanded in vitro using serum free medium supplemented with human platelet lysate (Capelli C et al, BMT, 2007; Capelli C. et al, Cytotherapy 2009). In vitro expanded MSC were produced in two officially authorized Cell Factories and tested in four Italian Hematology Units. The primary endpoint of this study was the safety. Secondary endpoints were the response of GvHD (evaluated 28 days after the last MSC infusion), as well as the overall survival and transplant-related deaths. Blood samples were periodically collected before and after MSC infusion to measure plasma levels of IL2Ralpha by ELISA, as previously described by our group (Dander E et al, Leukemia 2012). Results: Between August 2009, and June 2012, 47 patients (16 children, 31 adults, median age 25.5 years, range 1 to 67) were treated. The median dose of infused MSC was 1.5×106 cells per kg bodyweight. Enrolled patients presented with aGvHD in 37 cases, chronic overlap syndrome in 7 cases, and chronic classic GvHD in 3 cases. Fifteen pts had grade II GvHD, 23 grade III and 9 grade IV, according to NIH criteria. In 17 cases GvHD involved a single organ, in 24 cases 2, and in 6 cases 3 organs. Prior to MSC infusion 22 patients had received only high dose steroids, 12 patients received one cycle of pentostatin (1 mg/kg bodyweight for 3 days, Schmitt T. et al BMT, 2011: 46 580–585), while 13 received other conventional immunosuppressants. Patients received a median of 3 MSC infusions (range 1 to 8). No side effects were registered immediately after MSC infusion and no complications were lately referred as MSC-related. Overall, in 30 patients (63.8%) a clinical response of GvHD was registered. Thirteen of these patients (27.6%) had a complete response and 17 (36.1%) a partial response to treatment. Twenty-two of the 30 responding patients did not require further lines of immunosuppression after MSC infusion. Response was significantly more likely in patients exhibiting grade II GvHD versus those exhibiting more severe gradings (87.5% vs. 51.6%, p = 0.02) and in patients receiving MSC in a time interval of 30 days from the onset of GvHD (75.9% vs. 43.7%, p= 0.05). Current median follow up for this cohort is 200 days (range 30–1066). Responders show a significant lower transplant-related mortality (10.0% vs. 88.2%, p Measurements of plasmatic levels of IL2Ralpha, when comparing responders vs non-responders patients, showed a statistically significant difference in terms of fold decrease of the marker (p=0.027), corroborating clinical results. Similarly, a significant trend of fold decrease change (p=0.058) was observed when comparing responding patients receiving MSC within or after 30 days from the onset of the disease, in line with clinical results. Conclusions: This study confirms that human MSC prepared in academic cell therapy facilities may represent a safe and effective treatment of patients with steroid-refractory GvHD. Plasmatic inflammatory markers may help in evaluating and monitoring of clinical response. The sequential or combined administration of MSC and other immunosuppressants, such as pentostatin, is equally safe and feasible and deserves further investigation. We suggest to consider the use of MSC promptly, as early as possible, after steroid failure. Disclosures: No relevant conflicts of interest to declare.

Abstract 519 Introduction High-dose (hd) therapy with stem cell autograft is an effective treatment for both non-Hodgkin's (NHL) and Hodgkin's Lymphoma (HL). However, the occurrence of secondary malignancies, particularly myelodysplastic syndromes/acute leukemias (sMDS/AL), is a critical issue, representing a major cause of failure in patients potentially cured after hd-chemotherapy. Aim of the study To evaluate: frequency-cumulative incidence-risk factors, of both sMDS/AL and solid tumors 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. Patients received either the original or modified HDS regimens; PBPC were collected after hd-cyclophosphamide, and, in a subgroup, after a 2nd round of mobilization with hd-Ara-C. The series included 1,024 B-cell NHL, 234 HL and 89 T-cell NHL; there were 695 high-grade, 278 low-grade and 140 mantle-cell lymphoma; median age was 46 yrs; 57% were male. Overall, 640 (47%) patients received HDS front-line. Autograft was usually performed with PBPC (median CD34+ cells: 7×106/kg); most patients (n=774) received PBPC collected at the 1st mobilization course, whereas some others (n=298) were autografted with PBPC collected following a 2nd high-dose course. The Mitoxantrone/L-PAM combination was the most frequently employed conditioning for autograft (n=643), followed by BEAM (n=301); TBI-conditioning regimen was employed only in 79 patients. Results At a median follow-up of 7 yrs, the 5 and 10 yr Overall Survival (OS) projections are 64% and 56%, respectively. Among B-cell NHL, 70.5% of patients treated with Rituximab-supplemented HDS are presently alive vs. 55.6 of those treated with Rituximab-free HDS (p=0.001). Overall, 54 (4.0%) patients developed s-MDS/AL, with a cumulative incidence of sMDS/AL of 3.1% at 5 yrs and 4.6% at 10 yrs. (Figure 1A). Median time of s-MDS/AL occurrence was 3.2 yrs (range: 1.3-13.7) since autograft. In addition, 64 patients had a diagnosis of solid tumor, at a median time of 5.5 yrs (range: 0.5-14.6) since autograft. The cumulative incidence of 2ry-solid tumor is 2.5 % at 5 yrs and 6.6 % at 10 yrs. (Figure 1B). In univariate analysis, age >45 yrs., male sex and autograft with PBPC collected at the 2nd mobilization round had a significantly higher risk of sMDS/AL; a trend for a higher incidence was observed in patients receiving HDS with Rituximab (p=0.066) and in those presenting with BM involvement (p=0.097); on multivariate analysis, male gender and autograft with PBPC of the 2nd mobilization round were the only parameters associated with sMDS/AL occurrence (SDHR: 2.74, p=0.004 and 2.44, p=0.002, respectively). Concerning solid tumors, in univariate analysis, age >45 yrs, Rituximab addition to HDS, HDS with hd-Ara-C, and autograft with PBPC collected at the 2nd mobilization round had a significantly higher risk of solid tumor; on multivariate analysis, age >45 yrs., Rituximab addition and consolidation Radiotherapy following HDS were the only parameters associated with solid tumor occurrence (SDHR: 2.10, p=0.002, 1.99, p=0.011 and 2.13, p=0.024, respectively). Conclusions The incidence of sMDS/AL observed following HDS is among the lowest reported so far in lymphoma patients treated with hd-therapy and autograft. However, the risk of solid tumor occurrence can not be ignored. Among risk factors, male gender and the quality, rather than the quantity, of grafted PBPC are the strongest factors associated with sMDS/AL. Other factors, namely older age, Rituximab addition and consolidation Radiotherapy, are mainly associated with the development of solid tumors. Despite the increased risk of secondary solid tumor, addition of Rituximab resulted in significant improvements in the overall survival of patients undergoing HDS. Further analysis are required to understand the biological meaning of the variable association between risk factor and secondary malignancy development. Disclosures: Tarella: Roche: Honoraria, research financial support. Rambaldi:Roche: Consultancy, Honoraria.