Search

The Transplant Centers belonging to Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO) conducted a survey with the aim of evaluating the effect of SARS-CoV2 pandemic on the allogeneic transplant activity in Italy. The pandemic period from 1/3/2020 to 31/7/2020 was compared with the same period in 2019. Overall, in 2020 there was a 2.4% reduction in the number of allo-HCT cases compared to 2019. Interestingly, this deflection did not affect the acute leukemia cases (+5.7% in 2020). The use of peripheral blood-derived stem cells (+10.7%) and cryopreservation (97.4% of the centers) was highly adopted in 2020. Despite the sanitary emergency, almost all of the surveyed centers declared no impact of SARS-CoV2 pandemic on the transplant timing and outcomes, and the sanitary policy was positively evaluated by the majority of centers. The emergency measures ensured that only a minority of the allo-HCT patients had been infected by SARS-CoV2; however, a mortality of 42.1% among the allo-HCT patients hospitalized for COVID-19 was recorded. This survey gives us the information that the GITMO Group reacted positively to the pandemic. Thanks to the emergency strategies, the Italian allo-HCT activity continued safely, showing only a minor deflection and offering the same probability of cure to the transplanted patients.

The importance of donor-recipient human leukocyte antigen (HLA)-DPB1 matching for the clinical outcome of unrelated hematopoietic stem cell transplantation (HSCT) is controversial. We have previously described an algorithm for nonpermissive HLA-DPB1 disparities involving HLA-DPB1*0901,*1001,*1701,*0301,*1401,*4501, based on T-cell alloreactivity patterns. By revisiting the immunogenicity of HLA-DPB1*02, a modified algorithm was developed and retrospectively tested in 621 unrelated HSCTs facilitated through the Italian Registry for onco-hematologic adult patients. The modified algorithm proved to be markedly more predictive of outcome than the original one, with significantly higher KaplanMeier probabilities of 2-year survival in permissive compared with nonpermissive transplantations (55% vs 39%, P = .005). This was the result of increased adjusted hazards of nonrelapse mortality (hazard ratio [HR] = 1.74; confidence interval [CI], 1.19-2.53; P = .004) but not of relapse (HR = 1.02; CI, 0.73-1.42; P = .92). The increase in the hazards of overall mortality by nonpermissive HLA-DPB1 disparity was similar in 10 of 10 (HR = 2.12; CI, 1.23-3.64; P = .006) and 9 of 10 allele-matched transplantations (HR = 2.21; CI, 1.28-3.80; P = .004), both in early-stage and in advanced-stage disease. These data call for revisiting current HLA matching strategies for unrelated HSCT, suggesting that searches should be directed up-front toward identification of HLA-DPB1 permissive, 10 of 10 or 9 of 10 matched donors. (Blood. 2009; 114:1437-1444) RI Porfirio, Berardino/I-1988-2012

In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before allo-HSCT has not been established. We conducted a Phase II study to evaluate the tolerability and efficacy of clofarabine and treosulfan as conditioning regimen before allo-HSCT. The primary objective was to evaluate the cumulative incidence of nonrelapse mortality (NRM) on day +100. Forty-four patients (36 with acute myelogenous leukemia, 5 with acute lymphoblastic leukemia, 3 with myelodysplastic syndromes) were enrolled. The median patient age was 47 years, and the median duration of follow-up was 27 months. The conditioning regimen was based on clofarabine 40 mg/m2 (days -6 to -2) and treosulfan 14 g/m2 (days -6 to -4). Allogeneic hematopoietic stem cells were derived from a sibling (n = 22) or a well-matched unrelated donor (n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, rituximab, cyclosporine, and a short-course of methotrexate. The regimen allowed for rapid engraftment and a 100-day NRM of 18%, due mainly to bacterial infections. The incidences of grade II-IV acute GVHD and chronic GVHD were 16% and 19%, respectively. The rates of overall survival (OS), progression-free survival, and relapse at 2 years were 51%, 31%, and 50%, respectively. Significantly different outcomes were observed between patients with low-intermediate and patients with high-very high Disease Risk Index (DRI) scores (1-year OS, 78% and 24%, respectively). Our findings show that the use of treosulfan and clofarabine as a conditioning regimen for allo-HSCT is feasible, with a 78% 1-year OS in patients with a low-intermediate DRI score. However, 1-year NRM was 18%, and despite the intensified conditioning regimen, relapse incidence remains a major issue in patients with poor prognostic risk factors.

IntroductionReducing toxicities while preserving efficacy in allogeneic stem cell transplant (allo-HCT) remains a particularly challenging problem. Different strategies to enhance the antitumor activity without increasing early and late adverse toxicities of the conditioning regimens have been investigated.MethodsThe aim of “AlloTreo” prospective phase 2 clinical trial was to evaluate the efficacy and safety of a conditioning regimen based on Treosulfan (42 g/m2) and fludarabine (https://clinicaltrials.gov/ct2/show/NCT00598624). We enrolled 108 patients with hematological diseases who received a first allo-HCT between June 2005 and January 2011, inside the frame of this trial at our center. Median age at allo-HCT was 49 (21–69) years. Disease Risk Index was low in 14 (13%) patients, intermediate in 73 (67.7%), high in 17 (15.7%), and very high in 4 (3.7%). Donors were human leukocyte antigen (HLA)-matched related in 50 cases, 10/10-matched unrelated in 36, and 9/10-mismatched unrelated in 22. Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine-A and methotrexate. Anti-T-lymphocyte globulin (ATLG) was administered in patients receiving unrelated allo-HCT. Stem cell source was mainly peripheral blood stem cells (95%).ResultsConditioning regimen was well tolerated. Full donor chimerism was documented for most patients (88%) at day +30. At 12 years, overall survival (OS) was 41.7% (32.2%–50.9%), progression-free survival (PFS) was 31.7% (23%–40.7%), GvHD-free/relapse-free survival was 20.9% (13.7%–29.1%), cumulative incidence (CI) of relapse was 44.5% (34.9%–53.6%), and transplant-related mortality (TRM) was 22.5% (15.1%–30.9%). CI of acute GvHD grades II–IV was 27.8% (19.7%–36.5%) at 100 days; 12-year CI of chronic GvHD was 40.7% (31.3%–49.9%). Relevant long-term adverse effects were 10 secondary malignancy, 3 fatal cardiovascular events, and 1 late-onset transplant-associated thrombotic microangiopathy. Ten successful pregnancies were reported after allo-HCT. In multivariate analysis, older age (≥60 years) at transplant [hazard ratio (HR), 2.157; p = 0.004] and a high/very high disease risk index (HR, 1.913; p = 0.026) were significantly associated with a lower OS.ConclusionsOverall, our data confirmed the myeloablative potential and safe toxicity profile of full dose Treo (42 g/m2) especially for the younger population.

Background. Median age of occurrence of acute myeloid leukemias (AML) and myelodisplastc syndromes (MDS) is 65 years and older. Nevertheless, the use of allogeneic stem cell transplant (allo-HCT) has been historically limited to younger population, namely due to excess in non-relapse-mortality (NRM) in olders. Methods. In the present study, we analyzed all consecutive patients aged ≥ 65y diagnosed with AML (71, 81%) or MDS (19, 19%) who received transplants from adult donors at our center from January 2005 to December 2019. Results. Median age was 68.29y (65.02-76.54), 26pts (29%) aged ≥ 70y. Thirty-three (37%) pts received a HLA-matched donor. Conditioning regimen was myeloablative in 46pts (51%). The 3-year overall survival (OS) was 53+/-6%, and disease free survival (DFS) 45+/-6% (Figure 1). Day-100 and 3-year NRM was 17+/-2% and 29+/-2%, respectively. The 3-year CI of relapse was 22+/-2%. Day-100 CI of aGvHD was 21+/-2% for grade II-IV, 14+/-1% for grade III-IV. The 3-year CI of cGvHD was 35+/-3%, extensive 20+/-2%. In multivariate analysis, the Karnofsky Performance Status (KPS) < 90% was associated with lower OS (HR: 2.999, CI: 1.477- 6.691; p=0.002), DFS (HR: 3.155, CI: 1.593 - 6.250; p=0.001) and higher NRM (HR: 2.997, CI: 1.344-6.682; p=0.041). HCT-CI ≥ 3 was also associated with higher NRM (HR: 2.949, CI: 1.166-7.462, p=0.022,). Diagnosis of MDS and receiving a matched donor with PTCy were associated with longer OS (HR: 0.3440, CI: 0.1029-0.915; p=0.033; HR: 0.197, CI: 0.042-0.934; p=0.041).Conclusions. Age alone should not limit transplant eligibility for AML and MDS. KPS and HCT-CI proved to be useful for patient selection among the elderly. The use of HLA-matched donors with PTCy improved OS compared to ATG in our consecutive series.

IntroductionAllogeneic stem cell transplantation survivors are at a relevant risk of developing chronic GvHD (cGvHD), which importantly affects quality of life and increases morbidity and mortality. Early identification of patients at risk of cGvHD-related morbidity could represent a relevant tool to tailor preventive strategies. The aim of this study was to evaluate the prognostic power of immune reconstitution (IR) at cGvHD onset through an IR-based score.MethodsWe analyzed data from 411 adult patients consecutively transplanted between January 2011 and December 2016 at our Institution: 151 patients developed cGvHD (median follow-up 4 years). A first set of 111 consecutive patients with cGvHD entered the test cohort while an additional consecutive 40 patients represented the validation cohort. A Cox multivariate model for OS (overall survival) in patients with cGvHD of any severity allowed the identification of six variables independently predicting OS and TRM (transplant-related mortality). A formula for a prognostic risk index using the β coefficients derived from the model was designed. Each patient was assigned a score defining three groups of risk (low, intermediate, and high).ResultsOur multivariate model defined the variables independently predicting OS at cGvHD onset: CD4+ >233 cells/mm3, NK 3, IgA 3/mm3. Low-risk patients were defined as having a score ≤3.09, intermediate-risk patients >3.09 and ≤6.9, and high-risk patients >6.9. By ROC analysis, we identified a cut-off of 6.310 for both TRM and overall mortality.In the training cohort, the 6-year OS and TRM from cGvHD occurrence were 85% (95% CI, 70-92) and 13% (95% CI, 5-25) for low-risk, 64% (95% CI, 44-89) and 30% (95% CI, 15-47) for intermediate-risk, 26% (95% CI, 10-47), and 42% (95% CI, 19-63) for high-risk patients (OS pThe validation cohort confirmed the model with a 6-year OS and TRM of 83% (95% CI, 48-96) and 8% (95% CI, 1-32) for low-risk, 78% (95% CI, 37-94) and 11% (95% CI, 1-41) for intermediate-risk, 37% (95% CI, 17-58), and 63% (95% CI, 36-81) for high-risk patients (OS p = 0.0075; TRM p = 0.0009).ConclusionsIR score at diagnosis of cGvHD predicts GvHD severity and overall survival. IR score may contribute to the risk stratification of patients. If confirmed in a larger and multicenter-based study, IR score could be adopted to identify patients at high risk and modulate cGvHD treatments accordingly in the context of clinical trial.

Post-transplantation cyclophosphamide (PTCy) has emerged as a promising graft-versus-host-disease (GVHD) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) from haploidentical donors and more recently in matched donor transplants. Herein, we describe our real-life experience on 249 adult patients undergoing allogeneic HSCT, from HLA-matched related (MRD), HLA-matched unrelated (MUD), or mismatched related donors (MMRD). Patients received unmanipulated peripheral blood stem cells (PBSCs), using a GVHD prophylaxis with PTCy and sirolimus. Mycophenolate mofetil was added in MUD or MMRD. In the HLA-matched donor group (MRD, n = 48, MUD, n = 50), the cumulative incidence of grades II-IV and III-IV acute GvHD was 23% and 9% at 100 days, respectively. The cumulative incidence of chronic GvHD was 25% at 2 years, severe only for 5% of the patients. The cumulative incidences of relapse and transplant-related mortality (TRM) were 31% and 9% at 2 years, respectively. The 2-year overall survival (OS) was 72% and progression-free survival (PFS) 60%; the composite endpoint of GvHD/relapse-free survival (GRFS) was 52% at 2 years. In the haploidentical donor group (n = 151), we documented a cumulative incidence of grades II-IV and III-IV acute GVHD of 35% and 20% at 100 days, respectively, and a cumulative incidence of chronic GvHD of 39% at 2 years. We observed severe chronic GVHD in 15% of the patients. The cumulative incidence of relapse and TRM was 32% and 25% at 2 years, respectively. The 2-year OS was 48%, whereas PFS was 43%; GRFS was 28% at 2 years. However, more patients in the haploidentical group presented high/very high disease risk index (DRI) and higher HCT-comorbidity index. In patients classified in the low-intermediate DRI, 2-year GRFS was 53% in MRD, 65% in MUD, and 46% in haploidentical HSCT (P = .33). Sirolimus-PTCy platform deserves further investigation as an alternative to calcineurin-inhibitor–based GVHD prophylaxis for all donor sources. In patients presenting a low-intermediate DRI, this strategy translates in relevant survival independently from the transplant source.

Immunomodulatory drugs (IMiDs) are effective therapeutics for multiple myeloma (MM), where in different clinical settings they exert their function both directly on MM cells and indirectly by modulating immune cell subsets, although with not completely defined mechanisms. Here we studied the role of IMiDs in the context of autologous hematopoietic stem cell transplantation on the T cell subset distribution in the bone marrow of newly diagnosed MM patients. We found that after transplantation pro-tumor Th17-Th1 and Th22 cells and their related cytokines were lower in patients treated with IMiDs during induction chemotherapy compared to untreated patients. Of note, lower levels of IL-17, IL-22, and related IL-6, TNF-α, IL-1β, and IL-23 in the bone marrow sera correlated with treatment with IMiDs and favorable clinical outcome. Collectively, our results suggest a novel anti-inflammatory role for IMiDs in MM.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only cure for several patients with high-risk hematological malignancies. Recent advances in supportive therapies have significantly reduced the treatment-related mortality over the last decades. Nevertheless graft-versus-host disease (GvHD) still represents a major complication, and research is needed to achieve further progress in this area of transplantation. Moreover, although initial studies suggested relative equivalence, recent and large prospective studies showed higher rates of acute and chronic GvHD, and worse survival in allo-HSCT from unrelated donors (URD) compared with HLA-identical sibling donors. Following our encouraging results in haplodentical setting with the more recently post-transplantation cyclophosphamide (PTCy) and sirolimus as GvHD prophylaxis (Cieri et al, 2015), in this study we investigated whether the incorporation of low dose anti-thymocyte globulin (ATG) to PTCy and sirolimus GvHD prophylactic approach, may alleviate some of the increased alloreactivity associated with URD transplants. We retrospectively evaluated a cohort of 21 haematological patients receiving URD allo-HSCT in the San Raffaele Haematology and BMT Unit, from 2013 to 2015. All subjects had high-risk hematologic malignancies, with the most common diagnosis being myeloid diseases (52%). A total of 11 patients had active disease at HSCT, while 9 were in hematologic remission. Nine patients scored high according to disease risk index defined by Armand et al, 10 scored intermediate, while only 2 had a low disease score. Myeloablative conditioning consisted of treosulfan (14 g/m2/day) on days -6 to -4, fludarabine (30 mg/m2/day) on days -6 to -2, and melphalan (70 mg/m2/day) on days -2 and -1, followed by T-replete G-CSF-mobilized PBSCs (n=19) or BM grafts (n=2). Whether 12 patients received stem cells from HLA- matched URD (fully 10/10 HLA matched), the remaining 9 had one-locus HLA-mismatched from their donors. During conditioning patients received ATG-Fresenius 5 mg/kg per day IV on day -4 to -2. In vivo B-cell depletion was obtained by rituximab (i.v. 375mg/m2 given as a single dose on day -1). Postgrafting immunosuppression consisted of PTCy (50 mg/kg/day) on days 3 and 4. Sirolimus was given orally from day 5, and monitored to maintain a target therapeutic plasma level of 5-14 ng/ml. According to chimeric status and evidence of GVHD, the dosage of sirolimus was tapered during the second month post-transplantation, ending in complete withdrawal within the sixth month after HSCT. Mycophenolate mofetil (MMF) was initiated orally at 10 mg/kg t.i.d. on day 5 after HSCT, and withdrawn on day 30. Median follow up was 247 days (range 29-486) from HSCT. All patients were engrafted in a median time of 17 days (range, 14-51 days), with full donor chimerism achieved by day 30. Poor graft function was observed in 11 patients. Post-HSCT recovery of lymphocyte subsets was lengthy as compared to other unmanipulated HSCT, with a median time to CD3>100/ml of 41 days (range, 22-389 days) by flow-cytometry, while 5 patients never reached immune reconstitution. All except one developed febrile neutropenia during aplasia. We observed a high rate of serious infections: severe pneumonia in 7 cases (5 required NIV, 4 were admitted to ICU), CMV reactivation in 13 (3 CMV disease), HHV6 reactivation in 10, BK virus haemorrhagic cystitis in 2 patients. Although the overall mortality associated with these complications was limited, as evidenced by a favourable NRM, it caused significant morbidity in patients and often required aggressive therapies, potentially contributing to poor graft function. The incidences of acute and chronic GVHD were low. A grade II-IV acute GvHD was reported in 10% patients, while five patients developed chronic GvHD (mild in 4 cases, only one moderate). Non-relapse mortality (NRM) at 100 days and 1 year was 4.8% and 20.7%, respectively. The estimated 1-year overall survival (OS) and relapse incidence were 51% and 22.5% respectively. Although limited by a small number of patients with relatively short follow-up, our study suggests that URD allo-HSCT with ATG, PTCy and sirolimus-based GvHD prophylaxis, can be very effective in preventing GvHD, but at the expense of delayed immune reconstitution and high rate of infectious complications, while warranting acceptable NRM and relapse incidence. Disclosures Bonini: MolMed S.p.A: Consultancy.

BACKGROUND: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODS: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P

Introduction Allogeneic hematopoietic cell transplantation (HCT) is an effective therapeutic option for high-risk hematological malignancies; 80% of those who survive the first 2 years are expected to become long-term survivors. The prevalence of chronic health conditions approaches 75% among HCT survivors and that for severe or life-threatening conditions exceeds 20%. Patients and Methods A standardized follow-up of HCT survivors is applied at our Center, according to Jacie Standards. Here we report the analysis of data collected between July 2014 and July 2015 in 260 adult patients (pts) who underwent an HCT between 1992 and 2014. Data on 7 items - selected to monitor relevant comorbidities - were prospectively collected in our Institutional database. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results Pts characteristics are reported in table 1, median time of follow-up 4.4y (r1-22), cumulative follow-up 1404y; 13 pts deceased during the time of observation (6 due to disease relapse, 2 to late major infection, 2 to second cancer, 1 to GvHD, 1 to myocardial infarction, 1 unknown). - chronic Graft-versus-Host-Disease (c-GvHD): at a median follow-up of 43 months (r 16 months - 21 years) 84 (32%) pts are presenting c-GvHD features. According to NIH 2014 consensus criteria 23 cases were classified as mild, 32 moderate, 29 severe. Median number of involved organs 2 (r1-5), 39 pts were experiencing skin lesions, 55 eyes, 28 mouth, 19 joint and fascia, 18 lungs. Topical therapy was the treatment of choice for mild cases, while moderate and severe were treated with systemic therapy. The partnership with the lung specialist and the ophthalmologist was crucial for the management of lung and eyes GvHD. - Late infectious manifestation: 38 (15%) pts present late infection, 2 pts deceased due to major events. Of note pneumonia was reported in 12 pts, Varicella Zoster virus reactivation in 7, CMV late reactivation in 4 pts. - Second cancer screening was performed according to international guidelines. The incidence of new cases is 10% (26 pts) and 11 pts are actually under work-up for suspicious lesions. Non-melanoma skin cancer was the most frequent diagnosis (13 cases); 3 pts were diagnosed with cervix cancer, 2 with lung cancer. The prevalence of second cancer in our population is 18% (47 cases). All pts were treated according to standard for general population, 45/47 are alive. - Cardiovascular diseases were frequently observed in our setting: hypertension was documented in 36 pts, arterial diseases in 10 pts, cardiomyopathy in 28 pts. Overall 27% of pts were diagnosed with cardiovascular comorbidities. - Metabolic syndrome (MS) is reported as a very common complication in long-term survivors: 65 (25%) pts were presenting features of MS (3/5 among hypertension, dyslipidemia, raised fasting glucose, and central obesity). A concomitant thyroid dysfunction - requiring hormonal replacement - was present in 27/65 pts. - Secondary hemosiderosis was documented (with MRI and blood parameters) and treated in 39 pts (15%) - 8 pts received deferasirox while phlebotomy was used in 31. - Osteoporosis and bone loss were evaluated measuring bone mineral density using dual-energy X-ray absorptiometry; osteopenia was detected in 81 pts and osteoporosis in 42 (47%). Pts were evaluated in conjunction with the endocrinologist and treated according to the fracture risk score. According to donor source no difference were observed (Chi-square test - p ns) except for higher incidence of moderate/severe GvHD incidence in HLA identical sibling (p 0.0097) as compared to alternative donors. Discussion HCT survivors are at a defined relevant risk of developing long-term complications that have a direct impact on the morbidity and mortality.A multidisciplinary active screening within routine HCT long-term follow-up care is mandatory to enhance early diagnosis/treatment and overall outcome. The next challenge will be to enhance the primary prevention to reduce the incidence of preventable comorbidities. Table 1. patients characteristics N (range) Pts 260 Age At transplant 48y (10 - 76) At follow-up 54y (20 - 82) Male / Female 169 / 91 Diagnosis AML / ALL 106 / 33 MDS 27 HD / NHL 23 / 29 MM 14 CML 8 CLL 5 SAA / EPN 4 / 1 Others 10 Status at transplant CR / PD 169 / 91 Donor Haploidentical 100 HLA identical Sibling 76 Match Unrelated Donor 82 Cord Blood 2 Disclosures Bonini: MolMed S.p.A: Consultancy.

Background Optimization of pre-transplant risk assessment is a crucial issue to improve the allo-HSCT decision making process. Actually 3 major algorithms are in use in clinical practice: the EBMT risk score, the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and - more recently introduced - the refined Disease Risk Index (DRI). DRI was defined to calibrate HSCT outcome across studies and centers. It was developed as a tool to assign patients into risk groups based on disease type and status at the time of transplantation. The aim of the DRI is to provide a robust tool that can be used for prognostication, for the analysis and interpretation of retrospective data, whether conducted in single-center, multicenter, or registry settings, or within the context of the federally mandated center outcome reporting. The DRI can also be used for the stratification of patients entering prospective HCT clinical trials. DRI is not a fixed tool but instead it was conceived to be refined by the transplant community as new information becomes available. Here we are presenting the results of a retrospective study designed to evaluate the 3 aforementioned score in stratification and prognostication of transplant outcome after a haploidentical HSCT (haplo-HSCT). Patients and Methods We included 220 adult patients (pts - 138 male, 82 female) who underwent a haplo-HSCT for hematologic malignancies, between 2006 and 2014 and were reported to our Institutional database. Risk assessment score and outcome analysis included all consecutive pts receiving an haplo-HSCT as 1st allogeneic transplantation. Pts receiving haplo-HSCT as 2nd or 3rd HSCT were excluded from the present analysis. Median age was 49 years (range, 15-77). The cohort included a broad representation of diseases (138/220 acute leukemia, 30 Hodgkin lymphoma); 62 pts were in complete remission at transplant, 158 were presenting active disease. Conditioning regimens mostly rely upon the combination of treosulfan plus fludarabine (201/220) and total body irradiation (range 200 - 400 cGy) was utilized in 52 patients. GVHD prophylaxis consisted mostly of an mTor inhibitor (rapamycin) combined with mycophenolate mofetil. The majority of patients received peripheral blood stem cells from a family haploidentical donor as stem cell source, while only 4 patients received bone marrow transplant. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results The median follow-up for survivors was 37 months (r 6-107). The overall survival (OS) at 2-y was 35% and the transplant related mortality at 100-days 23%. The 2y OS according to EBMT / HCT-CI / DRI risk score are reported in table 1.a and figure 1. The evaluation of the HCT-CI impact after DRI stratification was able to show a significant difference in outcome showing better survival for pts with low DRI score and low HCT-CI score as expected (table 1.b). Discussion Refined DRI score and HCT-CI score predict survival after haplo-HSCT. The integrated application of refined DRI and HCT-CI may improve the definition of transplant eligibility for pts candidate to allogeneic HSCT form alternative donors including family haploidentical source. Table 1a. EBMT score 0-3 % pts 4-5 %pts > 5 %pts p 51% 17 34% 51 27% 32 0.07 HCT-CI score 0-2 3-4 >/= 5 48% 59 36% 31 0% 10 0.0001 DRI score Low-Intermediate High Very-High 61% 32 27% 51 5% 17 0.0001 Table 1b. HCT-CI 0-4 HCT-CI >/=5 p DRILow-Intermediate 64% 0% 0.0001 DRIHigh-Very High 29% 0% Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract 666 Background: Results of haploidentical stem cell transplantation (SCT) after standard extensive T-cell depletion for advanced leukemias are poor (Ciceri et al, 2008). In contrast, significant leukemia-free-survivals are produced after T-cell replete SCT from matched related, unrelated and cord-blood donors, even in advanced phases of disease (Kolb HJ, 2009). New protocols based on T-cell repletion are warrented in patients receiving haplo-SCT, in order to offer to all candidates patients with advanced leukemia the potential of cure of allogeneic SCT.Rapamycin is an immunosuppressive drug that arrests cell cycle in G1 phase through the inhibition of DNA transcription, RNA translation and protein synthesis. Morover, in contrast to calcineurin inhibitors, it promotes the generation and expansion of T regulatory cells (Tregs). Aim: We investigated the safety of infusion of T-cell replete unmanipulated peripheral blood stem cells (PBSC) from family haploidentical donor with a combination Rapamycin, Mycophenolate and ATG as GvHD prophylaxis, to preserve early Treg function (TrRaMM study, Eudract 2007-5477-54). Patients and Methods: Since 2007, forty-six patients underwent allogeneic transplantation for AML (25 pts), ALL (7 pts), sAML (6 pts), MDS (3 pts), CML-BC (2 pts), NHL (2 pts) or HD (1 pt). The median age was 50 years (range 14-69). At time of transplantation 5 pts were in early phase, and 41 were in advanced phase. Median time from diagnosis to transplantation was 351 days (range 81-1387); 8 patients were enrolled for relapse after allogeneic SCT from MRD or MUD. Median comorbodity index score was 1 (0-5). The conditioning regimen included Treosulfan (14 g/m2 for 3 days), Fludarabine (30 mg/m2 for 5 days) and an in vivo T and B-cell depletion, by ATG-Fresenius (10 mg/kg for 3 times) and Rituximab (a single 500 mg dose). All pts received allogeneic peripheral blood cells from an HLA-haploidentical related donor without any in vitro positive selection of CD34+ cells. GvHD prophylaxis consisted of Rapamycin (target level 8-15 ng/ml, till day +60) and MMF (15 mg/kg tid till day +30). Results: All patients engrafted, and all but eight were in disease remission at first marrow evaluation on day +30. Cumulative incidence of grade 2-4 aGvHD was 33% (95% CI: 18-48); cumulative incidence of grade 3-4 aGvHD was 12% (95% CI: 2-22). Interestingly, half of patients with GvHD developed it at immunosuppressive prophylaxis withdrawal for disease relapse. Only six patients developed cGvHD. Cumulative incidence of TRM and relapse incidence were 26% (95% CI: 11-41) and 53% (95% CI: 35-71) respectively. None developed EBV reactivation. Patients experienced an early and sustained immunoreconstitution with a median 221 circulating CD3+cells/μL (range 43-1690) from day 30. The immune-reconstitution was polarized towards central memory cells (CD45RA-CD62L+ cells 32.7% ± 4.8) that produced IL-2 (IL-2+ cells 26.2% ± 5.3). Of interest, at day +90 from transplant, Tregs were significantly expanded (CD4+CD25+CD127-Foxp3+ cells 15.6% ± 4.8 on total CD3+ cells, P Conclusions: Rapamycin-Mycophenolate-ATG are effective to prevent GvHD in T-cell replete unmanipulated haploidentical peripheral stem cell transplantation for advanced haematological malignancies. This associates with an early T-cell immunoreconstitution characterized by the in vivo expansion of early-differentiated T cells and Tregs, and translates in promising leukemia-free survival in patients with advanced resistant leukemia. Further studies are warranted to gain insight on the role of rapamycin as platform for exploitation of Tregs in allogeneic HSCT from mismatched donor. Disclosures: No relevant conflicts of interest to declare.

Abstract 2385 Background. Allogeneic haemopoietic stem cell transplantation (HSCT) is the best therapeutic option for high-risk hematological disease (HRHD), particularly acute myeloid and lymphoblastic leukemia (AML/ALL). A widely application of HSCT is limited by lack of availability of a suitable donor for every candidate patients (pts). In order to offer a donor to every candidate pts, several centers had developed in the last decade alternative strategy of HSCT, such as umbilical cord blood (UCB) or family haploidentical HSCT (haplo-HSCT). With the aim to treat high-risk leukemia in the ideal appropriate time by allogeneic HSCT, we adopted a policy relying upon HLA typing at entry of every pts diagnosed with HRHD, followed, in absence of a MRD, by the prompt activation of the MUD search. Patients lacking a MRD or a MUD at the appropriate timing are proposed for haplo-HSCT. Methods. Here we report an intention-to-treat analysis of alternative donor HSCT at our Institution for pts diagnosed with high risk AML or ALL. Data were obtained from local institutional database. Results. Between Jan-2004 and July-2010 241 pts (median age 48y, r 15–72) with diagnosis of ALL (60 pts; median age 33y, r 15–64; male 39) or AML (181 pts, median age 51y, r 19–72; male 83) were defined as “high risk status” and received an indication to HSCT according to EBMT (European Group for Blood and Marrow Transplantation) and Northern Italy Leukemia Group (NILG, www.nilg.it) recommendations. In the ALL group 3 pts died before proceed to HSCT, 5 pts are waiting for the identification of a donor. Overall, 52/60 (86%) pts underwent HSCT, the status of disease at transplant was of complete remission (CR) for 27 pts, persistence of disease (PD) for 25. In the AML group 6 pts died before proceed to HSCT, 15 pts are waiting for the identification of a donor. Overall, 160/181 (88%) pts underwent HSCT, the status of disease at transplant was of CR for 97 pts, PD 63. Overall 92 pts activated the research of a MUD, 42 proceed to transplant, 7 received a UCB, 26 received a haplo-HSCT due to absence of a suitable donor in the appropriate time frame or failure to met the criteria to engage a MUD donor. The median time from diagnosis to registry activation was 69 days (r 5–876), the median time from activation to transplant 84 days (r 28–348). In the group of pts in CR at transplant, 37 underwent HSCT from a MRD and 36 from a MUD, 4 pts received a UCB and 47 a haplo-HSCT. Seventy-two pts are alive and in CR at last follow-up, 3/72 after a second transplant from a different donor (haplo-HSCT) and 3/72 after chemotherapy and adoptive immunotherapy to treat hematological relapse. Fifty-two pts died and the causes of death were: relapse (27), infection-related (19), graft-versus-host-disease (GvHD; 5), acute myocardial infarction (1). In the group of pts in PD at transplant, 16 underwent HSCT from a MRD and 6 from a MUD, 3 pts received UCB and 63 a haplo-HSCT. Fifteen pts are alive, 14 in CR, 1 pts under adoptive immunotherapy; 1/14 pts received a second transplant from a different donor (haplo-HSCT) to treat hematological relapse. Seventy-three pts died and the causes of death were: relapse (43), infection (23), GvHD (7). Overall, the median survival is 382 days and the median follow-up for pts alive is 548 days. The 1-year overall survival (OS)/transplant related mortality (TRM)/relapse incidence (RI) are 50,76% 26,96% and 40% respectively. For pts transplanted in CR the 1y OS/TRM/RI are 77,2%, 20,01% and 25% respectively. The outcome analysis per donor source (MRD vs MUD vs haplo-HSCT) is comparable (p=ns). For pts transplanted in PD the 1y OS/TRM/RI are 19,7%, 41% and 67% respectively. The outcome analysis per donor source (MRD vs MUD vs haplo-HSCT) shows a trend of lower RI and TRM in the haplo-SCT vs MRD. Conclusion. The policy adopted provided an allogeneic HSCT in > 80% of candidate high-risk acute leukemia patients. No significant differences were registered in outcome for patients transplanted from matched-related, unrelated or family haploidentical donors. Further evaluation and a long-term follow-up will add important evaluation in term of long-term disease control and long-term toxicities. Disclosures: Bonini: MolMed: Consultancy. Bordignon: Molmed: Employment.

Abstract 2382 Background. Allogeneic transplantation of haemopoietic stem cells (allo-SCT) from an HLA- matched related (MRD) or unrelated donor (MUD) is a curative option for patients (pts) with high-risk haematological disease (HRHD). In the absence of a MRD or MUD, pts have been offered investigational transplant strategies such as umbilical cord blood (UCB) or family haploidentical SCT (haplo-SCT). In our Institution, all patients with HRHD are typed at entry; if a suitable MRD donor is missing a MUD search is promptly activated through the Bone Marrow Donors Worldwide Registry (BMDW). Our policy is to offer an haplo-SCT to adult pts lacking an MRD or MUD in order to adequately treat HRHD in the ideal appropriate time according to clinical indications for allo-SCT. This policy is based on our ongoing protocols for primary disease. Methods. Here we report the intention-to-treat (ITT) analysis of alternative donor transplantation at our Institution. Data were obtained from Institutional database; all HRHD patients were included in analysis. Results. Between Jan-2004 and July-2010, 410 pts (100% of the following ITT analysis; median age 48y, range 15–76, 91 pts over-60y; male 264) received indication to allo-SCT according to EBMT recommendations. The majority of pts presented with a diagnosis of acute leukaemia (15% lymphoblastic, 45% myeloid), while 12% presented with non Hodgkin lymphoma, 8% myelodysplastic syndrome, 6% Hodgkin disease, 5% multiple myeloma, 2% chronic myeloid leukaemia, 2% chronic lymphocytic leukaemia, 2% severe aplastic anaemia, 1% primary myelofibrosis, 2% others. Eighty-nine pts (22%) received a transplant from a MRD; 190 pts (46%) activated an MUD search in the BMDW registry; 84 pts (20% of total pts, 44% of MUD searching) received a MUD transplant; 42 pts (10%-21%) received an haplo-SCT due to lacking of a suitable MUD in the appropriate timing according to disease status, or absence of suitable criteria to engage a MUD donor; 11 pts (3%-6%) received a UCB if lacking a suitable haplo donor. Overall, 149 pts received an haplo-SCT (36%): 42 after BMDW research, 107 up-front. Twenty-one pts died before receiving a transplant (5%), 37 (9%) are still searching for a suitable donor and an eligible donor is under final evaluation for 19 pts (5%). One-hundred-fifty pts underwent transplant in complete remission (CR), 12 in early phase, 9 in very-good-partial remission (VGPR), 7 in partial response (PR), while 155 were in progression of disease (PD). The median time from diagnosis to transplant was 165 days, the median time from MUD search to transplant 103 days (range 28–824 days). The overall survival (OS) analysis in intention to treat is 51% at 1 year, 39% at 3y; the 1y and the 3y OS for pts transplanted in CR/early phase/VGPR are 74% and 57% respectively, for the pts transplanted in PR/PD 29% and 21% (p At last evaluation 149 pts are alive, with a median follow-up of 802,5 days (range 2–2315); 93/149 received transplant in CR, 10 in early phase, 6 in VGPR, 3 in PR, 37 in PD. Twenty out of 149 experienced disease relapse and were rescue with salvage treatment and adoptive immunotherapy in 15 cases, while 5 pts received a second transplant from a different donor. Up to 155 pts transplanted in PD, 37 (24%) are alive with a median follow-up of 499 days, of these 22 pts received a haplo-SCT, 8 MUD, 6 MRD, 1 UCB. The median follow-up for pts dead is of 118 days (range 2–2315), the cause of death were disease relapse (53,26%), graft-versus-host-disease (8,7%), infection (31,5%), multi organ failure (3,8%), cardiovascular disease (1,09%), haemorrhage (1,63%). Conclusion. In ITT analysis, 81% of overall pts candidate received an allo-SCT (59% from an alternative donor, 22% from a MRD) and the outcome achieved for pts transplanted in CR is comparable within the three major donor source (MRD – MUD – haplo-SCT). This result confirm the need to offer to every candidate pts a transplant option in the appropriate time, but also support the use of alternative donors, particularly haplo-SCT, in absence of an available MRD or MUD. The highly committed policy performed in the alternative-SCT setting and the implementation of an alternative donor option are essential prerequisite to obtain these results, offering to every candidate pts a concrete opportunity of treatment. Disclosures: Bordignon: Molmed: Employment.