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Astolf et al provide the first report of acute promyelocytic leukemia driven by viral insertion into the RARA locus. This represents a clear demonstration of a pathology driven by the member of the anelloviruses, a group of viruses otherwise thought to have minimal or no pathogenic potential.

BACKGROUND: Many efforts have been made in the attempt to address the conundrum question of fitness definition ad prognosis prediction in elderly acute myeloid leukemia (AML) patients. Parametric definitions are expected to give an advantage in patient stratification; however, clinical examination remain de facto pivotal to formulate therapy decisions and frequently the comorbidities are empirically evaluated. METHODS: We conducted a multicenter study collecting baseline comorbidity, laboratory data, CTCAE 4.0.3 adverse events (AE), and outcome of elderly patients (>65 years old) with new onset AML who received hypomethylating agents as 1st line therapy. We tested the impact on prognosis of baseline clinical and biological risk factors. Furthermore, we evaluated a score - acute myeloid leukemia-composite model, AML-CM (Mukherjee et al, 2017) - developed in chemotherapy-eligible patients, that accounts for baseline comorbidities, laboratory parameters, age and cytogenetic-molecular risk. The study was approved by local Ethical Authority (316/2019/Oss/AOUBo). RESULTS: We collected data from 131 consecutive elderly patients who received 1 st line HMAs between January 2008 and January 2021. Patients had a median age of 76 years (IQR 72 -79). Seventy-seven out of 131 patients (58.8%) had de novo AML, 32/131 (32.8%) had secondary AML, and 11/131 (8.4%) had therapy-related AML. Out of 123 evaluable patients, 43 (34.9%) had complex karyotype, 1 (0.8%) inv(16), 59 (48.4) normal karyotype, 18 (14.7%) other alterations; 8/108 patients harbored FLT3 ITD mutation (7.4%, 23 not tested), 12/101 NPM1 mutation (11.9%, 30 not tested). Based on these data, 111 patients were evaluable for ELN2010 risk stratification; 9 over 111 patients (8.1%) were stratified in the low risk, 42/111 (37.8%) in intermediate-1 risk, 17/111(15.3%) in intermediate-2 risk, and 43/111 (38.7%) in high-risk class. As expected, most of the patients had at least one comorbidity. Particularly, baseline arrhythmia was present in 29/130 (22.1%, 1 no data), cardiovascular comorbidity in 20/130 (15.4%, 1 no data), diabetes in 20/131 (15.3%), cerebrovascular comorbidity in 11/131 (8.4%), kidney disease in 15/130 (11.5%, 1 no data), lung chronic disease 19/130 (14.6% 1 no data), hypoalbuminemia in 25/111 patients (22.5%, 20 no data). With a median follow up of 28.2 months, median overall survival (OS) of the entire cohort was 15.8 months (95% C.I. 11.2-19.4). We confirmed that patient who obtained a response (complete remission, partial response, hematological improvement) after 2 months of therapy had the best OS (figure A, median OS of 21 months for responders vs 7.4 months for non-responders, p To test the impact of comorbidities combined with cytogenetic and molecular risk, AML-CM was used. Our results indicate that AML-CM score was able to stratify prognosis in elderly patients receiving frontline HMAs (figure B, median OS in score group 1: 29.7 months, score group 2: 16.5 months, score group 3: 11.2 months, score group 4: 6.6 months, p=.038). The worse prognosis of patients with higher AML-CM score, which includes patients with increased baseline comorbidities, may be explained with a higher incidence of AEs (84.55, 116.01, 131.45, 229.3 events for 100 patients per year for score group 1,2,3, and 4, respectively) and infections (53.80, 55.10, 85.95, 140.13 events for 100 patients per year for score group 1,2,3, and 4, respectively), in patients with higher baseline comorbidities. CONCLUSION: In this study we found that baseline comorbidities, captured by AML-CM score, may define prognosis of elderly patients receiving 1st line HMAs; parametric comorbidity scores may improve our ability to predict outcome and tailor interventions. The impact of comorbidity on OS may be increased with novel and more aggressive therapy. For this reason, specific studies on functional fitness tests and geriatric assessments are highly warranted in patients receiving HMAs plus venetoclax. This work was supported by Bologna AIL. CP and AC shared last authorship. Figure 1 Figure 1. Disclosures Martinelli: Daichii Sankyo: Consultancy; Pfizer: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Roche: Consultancy; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Cavo: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Papayannidis: Pfizer, Amgen, Novartis: Honoraria. Curti: Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees.

Introduction In the setting of clinical trials Venetoclax (VEN) combined with hypomethylating agents (HMAs) has shown fair activity in Relapsed/Refractory (R/R) AML and impressive results in newly diagnosed (ND) elderly AML patients. However, no clear guidelines are available on real-life management, especially in the outpatient setting. This study involving AML patients treated with VEN combined with HMAs aims to amelioratate physicians' knowledge about the administration of these regimens. Methods This is a single-center retrospective study involving AML patients treated with Venetoclax combined with HMAs. Data were collected in accordance with GCP and Helsinky declaration. Adverse events (AEs) were graded according to CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results A total of 59 AML patients, 43 R/R and 16 ND, have been treated with VEN plus HMAs from March 2018 to June 2021 and completed at least 1 therapy course (range 1-9, median 2, IQR 1.0 - 4.0). The median age was 70 (range 22-88) years and 15.3 % had a documented ECOG score greater than 1. VEN was combined with azacitidine in 35/59 (59.3 %) patients and with decitabine in 22/59 (37.3 %) patients (Table 1: patient and disease characteristics). The majority of patients (40/59, 67.8 %) (28/43 R/R, 12/16 ND) received the first cycle as out-patients, 19 out of 59 (32.2 %) patients were hospitalized and used as control. No significant differences with regards to disease and patients' characteristics were observed between in- and out-patients. During the ramp-up phase only 2 cases of tumor lysis syndrome (TLS) and 5 AEs were documented. During the first course, a total of 54 AEs were recorded and experienced by 16 over 19 hospitalized patients (84.2 %) and 20 over 40 outpatients (50 %). The 30-day and 60-day mortality were 2.5% (1/40) and 20 % (8/40), respectively, among patients receiving first course as out-patents, comparable to those documented in hospitalized patients. Overall, we reported 118 AEs, of which 74 were grade III-IV and the most common were hematological 23/74 (31.1 %) or infective 41/74 (55.4 %). Regarding infections, at least one bacterial infection was experienced in 10/40 (25%) and 12/19 (63.1%) patients of the outpatient and hospitalized cohorts, respectively (p = 0.009, IC 1.37 - 19.74, OR 4.98). Pneumonia and sepsis (13 and 18 cases) were the most frequent infections. Sepsis incidence was higher among hospitalized patients (13/19, 68.4 %, vs 5/40, 12.5 %, p = 0.000029). No significant difference in infective risk was documented between R/R and ND patients (65.1 vs 50 %). Thirty-two out of 59 (54.2 %) patients experienced at least one VEN withdrawal due to treatment toxicity. Twenty out of 43 AEs requiring VEN suspensions occurred during the first cycle. Patients treated in-patient showed the tendency for a higher probability to suspend therapy due to treatment toxicity (10/19 IN vs 10/40 OUT, p = 0.04). While twenty-three out of 59 (38.9 %) patients were hospitalized for treatment complications at least once, the average number of days spent in hospital was significantly different between patients receiving the first course as outpatients as compared to those who were hospitalized (5.9 vs 39.7, respectively, p < 0.0001). With a median follow-up of 117 days (IQR 92 - 173.75) in ND patients the Overall Response Rate (ORR), defined as CR + CRi + HI, was 62.5 % (10/16), with a CR/CRi rate of 50 % (8/16) and a median OS of 247 days (95% C.I. 177.71- 316.58)(Fig 1a). In the R/R setting the ORR rate was 41.8 % (18/43), with a CR/CRi rate of 25.6 % (11/43) and a median OS of 219 days (95% C.I. 91.8 - 346.2) (Fig 2a). No differences in OS were documented between patients who underwent VEN plus HMAs outpatient and patients who underwent the first cycle hospitalized (p = 0,38) (Fig. 1b-2b). Conclusions With the limitations of a single-center retrospective study, our real-life data indicate that VEN plus HMAs is feasible in an outpatient management, with minimal TLS rate and no limiting toxicities. Of note, infections rate was acceptable, bacterial infections and sepsis risk were lower in outpatients than in hospitalized patients. There was no significant impact of the outpatient management on treatment effectiveness, with data in line with published AML cohorts. Further studies evaluating the clinical, social and economic impact of outpatient VEN-based treatments are highly warranted. Figure 1 Figure 1. Disclosures Papayannidis: Pfizer, Amgen, Novartis: Honoraria. Cavo: Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Background Although much efforts have been made to precisely define fitness of AML patients, in patients who are not candidate to chemotherapy, there is no prognostic model and the respective weight of AML biology and patient fitness are not well established. Here we test AML-CM score (Sorror, JAMA 2018), that is validated in fit population, in a set of old AML patients who received HMAs. Methods We retrospectively collected data of consecutive patients who received HMAs in our institution from 1st Jan 2008 with an age > 65 years at AML diagnosis. AML-CM score was applied to all the patients. Patients were divided in 4 groups (score 1-4: group 1, score 5-6: group 2; score 7-9: group 3, score > 9: group 4) and in 2 macro-groups (score 1-6: group A and score > 6 group B) for the analyses. Descriptive data are presented as median with interquartile ranges (IQR). Adverse events are graded according to CTCAE v4.03. Survival analysis was conducted with Kaplan-Meyer and are presented as 95% confidence intervals (C.I.) and differences in overall survival (OS) were tested with 2-side log rank test. Fisher exact test and Person's chi squared test were used whenever appropriate. Results At data cut-off, 1st Jan 2019, 60 consecutive patients received decitabine or azacytidine as 1st line therapy for AML. Median age of the population was 75.94 years (IQR 72.53-80.38). Most of the patients (37/62, 59.7%) had de novo AML, 19/62 (30.6%) had AML secondary to previous myeloid disorders and 6/62 (9.7%) had AML secondary to chemotherapy or radiotherapy. Most of the patients were smokers (19/33, 57.57%, 29 no data), and few were usual drinkers (4/16, 25.00%, 46 no data). In our set, out of 62 patients, 2 patients (3.2%) had inv(3), 1 (1.6%) a translocation involving 11q23, 1 (1.6%) del(5q), 4 (6.4%) mon(7) or del (7q), 1 (1.6%) del(17p), 15 (24.2%) complex karyotype, 27 (43.5%) normal karyotype, 4 (6.5%) other alterations and 5 were not evaluable; 3/17 (17.65%, 45 no data) harbored IDH2 mutation, 1/16 (6.25%) IDH2 mutation, 2/33 FLT3 mutation (6.06%, 29 no data), 1/24 (4.17%, 38 no data), 2/15 (13.33%, 47 no data) TP53 mutation. According to ELN 2017, 3/62 patients (4.83%) had low risk, 34/62 (54.84%) intermediate risk and 23/62 (37.10%) high risk AML. According to AML-CM score, 13/62 patients (20.97%) were in group A, 20/62 (32.36%) in group B, 21/62 (33.87%) in group C, 6/62 (9.68%) in group D, 2/62 (3.23%) were not allocated for incomplete AML-CM score. There was no difference in term of age, ELN risk, secondary AML prevalence, HMA administered, or response to HMA according to ELN criteria between group 1, 2, 3, 4 or between macro-group A and B. Cardiovascular comorbidity, diabetes mellitus, obesity, previous tumor, hypoalbuminemia, elevated LDH were prevalent in higher risk AML-CM groups (3-4) and in macro-group B. Median OS was 658 days (95% C.I. 316-1000) in group 1, 556 days (95% C.I. 463-649 in group 2, 243 days (95% C.I. 153-353) in group 3, 107 days (95% C.I. 47-167) in group 4 (p=.021, figure 1A). Furthermore, we observed a median OS of 589 days (95% C.I. 328-850) in macro-group A and 219 days (95% C.I. 96-342) in macro-group B (p=.003, figure 1B). Reduced survival was correlated with a non-statistical trend toward augmented incidence of infections and adverse events in higher risk AML-CM groups (3-4). Conclusions AML-CM is a useful indicator of prognosis in old patients that receive HMAs. Prognosis in our set is influenced by comorbidity (measured with AML-CM, a quantitative score) more than by disease biology. We identified a group of patients (macro-group A) that has median OS after HMAs outlying OS reported in literature. This brilliant result can be due to lower comorbidity. AML-CM could help in defining candidate patients for therapy intensification and care utilization or for team comorbidity management. GM and RDN equally contributed Figure 1 Disclosures Martinelli: Roche: Consultancy; Novartis: Consultancy; ARIAD: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Papayannidis:Pfizer: Honoraria; Teva: Honoraria; Shire: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Incyte: Honoraria. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Item does not contain fulltext Graft-versus-host disease in its acute (aGvHD) or chronic form (cGvHD) remains the most important posttransplantation factor influencing outcome after allogeneic hematopoietic stem cell transplantation (HSCT). It increases transplantation-related mortality (TRM) but reduces risk of relapse. The net effect of these 2 discordant effects determines survival. In view of current interests to exploit graft-versus-leukemia (GVL) effects, we analyzed 4174 HLA-identical sibling transplantations for chronic myeloid leukemia in first chronic phase, depending on the presence or absence and severity of GvHD with a landmark analysis. During the first 100 days, only aGvHD grades III and IV had an impact on TRM. During the time period day 100 to 3 years increasing severity of aGvHD is associated with increased TRM and decreased relapse incidence (RI) with hazard ratios (HRs) for TRM as follows: grade 0, HR = 1.0; grade I, HR = 1.52 (1.19-1.96); grade II, HR = 2.48 (1.95-3.14); grade III, HR = 5.76 (4.44-7.48); grade IV, HR = 14.7 (10.9-19.9) and likewise for RI: grade I versus 0, HR = 0.94 (0.76-1.16); grade II, HR = 0.60 (0.46-0.77); grade III, HR = 0.48 (0.29-0.81); grade IV, HR = 0.14 (0.02-0.99). Beyond 3 years, TRM and RI are determined by cGvHD. Limited cGvHD reduces RI to the same extent as extensive cGvHD but has no impact on TRM and, hence, results in best survival with an HR = 0.48 (0.32-0.71). aGvHD grade I has the highest likelihood of subsequent limited cGvHD, which results in cumulative incidence estimates of survival at 10 years being best for patients with initial aGvHD grade I: survival at 10 years grade 0 = 59%, I = 63%, II = 56%, III = 26%, IV = not applicable. These data clarify the role of GvHD in posttransplantation outcome. Considerations for long-term outcome are essential when short-term data of interventions on GvHD are analyzed.

Hepatitis B virus (HBV)-infected individuals are occasionally used as donors for bone marrow transplantation (BMT). We studied the rate of HBV infection and the clinical expression of the associated liver disease in patients receiving marrow from HBsAg+ donors. We performed a retrospective survey in 14 BMT units in Italy in which all BMTs performed between 1984 and 1994 were reviewed and those involving HBsAg+ donors were identified. Donors and recipients were analyzed for HBV markers and liver disease. A total of 24 of 2,586 patients (0.9%) had received an HBsAg+ marrow. HBsAg became detectable in 22% of pre-BMT HBsAg-patients, but only 5.5% became chronic HBsAg carriers. Antigenemia developed more frequently in anti-HBs-compared with anti-HBs+ patients independently of passive prophylaxis with hyperimmune anti-HBs Ig, although the difference was not significant. Severe liver failure with death occurred in 21% of patients, which was a value greater than that generally observed after BMT in our units (3.7%). Patients with an anti-HBe+ donor had higher frequency of liver failure (28% v 0%) and alanine aminotransferase peaks as compared with those of patients with an HBeAg+ donor. Liver failure was not observed in anti-HBs+ recipients. The use of HBsAg+ donors, particularly if anti-HBe+, increases the risk of severe liver disease in BMT recipients. Anti-HBs positivity may prevent severe liver damage.

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Allogeneic stem cell transplantation (allo-SCT), which provides a tumor-free graft, is an alternative approach to autologous transplantation for multiple myeloma (MM) that offers the possibility of cure through a graft vs myeloma effect (GVM). However, the inherent non relapse mortality (NRM) and the high post-transplant relapse rate are the major shortcomings of this strategy which continues to have a controversial role in MM treatment. To highlight the long-term clinical outcomes of allo-SCT, we performed a retrospective analysis on 102 patients (pts) with MM who received at our Institution either a myeloablative (MA) (74 pts) or a non-myeloablative (NMA) (28 pts) conditioning regimen between 1990 and 2014. The MA regimen consisted in low dose TBI and cyclophosphamide (cyclo) ± melphalan (mel) or busulfan-cyclo. The NMA regimen was mel-fludarabine. Graft versus host disease (GVHD) prophylaxis consisted in cyclosporine + methotrexate (83%) or mycophenolate (17%), with the addition of thymoglobulin for unrelated or related female vs male recipient donors. The median age was 42 yrs (IQR 38-47), 60% pts were male. The hematopoietic cell donors were sibling in 77 pts and unrelated in 25, while the source of stem cells was peripheral blood in 65 and bone marrow in 37 pts. Fifty-six pts received allo-SCT as first-line therapy, 31 as second-line and 13 as third or fourth-line. Median time from diagnosis to allo-SCT was 22 months. Response status at the time of transplant was at least PR in 63% of the pts, including ≥ VGPR in 36% and CR in 12%. Overall, the response rate after allo-SCT was as follows: CR 58%, VGPR 19%, PR 18%. Median CR duration was 10 years (44% at 15 years). The incidence of acute grade II-IV and III-IV GVHD was 25% and 15%, respectively. The incidence of all grades chronic cGVHD was 48%, grade ≥2: 24%, with a median onset time of 178 days. By competitive risks analysis, the cumulative incidence of cGVHD at 1 and 3 years was 20% and 32%, respectively. On univariate analysis, the gender combination of female donor-male patient resulted in significantly higher incidence of cGVHD (sub hazard ratio, SHR, 2.3, P= 0.03). The cumulative incidence of NRM was 6.6% at 100 days, 11% at 1 year and 14.4% at 3 years, with lack of statistically significant relationship with the conditioning regimen. By univariate analysis, < PR prior to allo-SCT (SHR 2.8) and all grades cGVHD (SHR 4.6) were significantly associated with an increased NRM. By competitive risks analysis, the cumulative incidence of relapse was 50% at 5 years, 58% at 10 years and 59% at 15 years. On univariate analysis, sibling donor (SHR 0.54, P=0.047), all grades cGVHD (SHR 0.5, P=0.011) and ≥VGPR after allo-SCT (SHR 0.38, P=0.001) were significantly associated with extended time to progression. All grades cGVHD (SHR 0.43, P=0.005) and ≥VGPR after allo-SCT (SHR 0.36, P= 0.001) were independent predictors for a lower risk of progression on multivariate analysis. With a median follow-up of 13 years, overall survival (OS) was 43% at 5 years and 34% at 10 years. In univariate analysis, low ISS stage at diagnosis, sibling donor, absence of female donor-male patient gender combination, ≥VGPR prior to allo-SCT and first-line allo-SCT were significantly related to OS. Multivariate analysis confirmed an OS benefit for having a sibling donor (HR 0.30, P In conclusion, this retrospective analysis performed with an extended follow-up of 13 years shows that a fraction of MM pts can be long-term survivors after allo-SCT, one third of them being potentially cured. The best outcomes were obtained when allo-SCT was applied in pts in an early phase of their disease and with a small residual tumor size. The major challenge, both with MA and NMA allo-SCT, was the relatively high post-transplant relapse rate. The presence of cGVHD was protective for the risk of progression, supporting the role of GVM, but increased the risk of NRM. New approaches aimed at modulating cGVHD are warranted. In addition, incorporation of novel agents before and after allo-SCT to increase the rate and duration of high-quality responses, as well as identification of those patients mostly benefiting from this procedure, will likely contribute to improve long-term outcomes. Disclosures Zamagni: Celgene Corporation: Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Cavo:Sanofi: Consultancy, Honoraria; Onyx: Honoraria; Jansenn: Consultancy, Honoraria; Millenium Pharmaceuticals: Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Honoraria.

Using the European Group for Blood and Marrow Transplantation (EBMT) registry, we retrospectively studied 19 patients with AL (amyloid light-chain) amyloidosis who underwent allogeneic (allo; n = 15) or syngeneic (syn; n = 4) hematopoietic stem cell transplantation (SCT) between 1991 and 2003. For allo-SCT, full-intensity conditioning was used in 7 patients and reduced-intensity conditioning (RIC) in 8 patients. Engraftment was durable in 12 of those 15 patients. The median follow-up time is 19 months. Kaplan-Meier probabilities of overall and progression-free survival were 60% and 53% at 1 year, respectively. Overall, 40% of patients died of transplant-related mortality (TRM). Best hematologic response after SCT was complete remission (CR) and partial remission (PR) in 8 and 2 patients, respectively, leading to an organ response in 8 of these patients. Seven of the 10 patients in remission are long-term survivors. In 5 of 7 evaluable patients in CR, chronic graft-versus-host disease (GvHD) was observed, indicating the contribution of immune effects to disease control. The main clinical problem was cardiac failure in patients with poor performance status due to amyloidosis or in combination with severe infections. These data suggest that allo-SCT might be a promising and potentially curative treatment modality for selected patients with AL amyloidosis.

Background: Autologous stem cell transplantation and the development of new agents with potent anti-tumor activity have considerably improved the survival of multiple myeloma (MM) patients. However, there is still a high risk of relapse mainly due to the inability of these agents to cure and eliminate definitively the MM cells. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment particularly for patients with high risk factors but its use is still controversial. We recently demonstrated in a prospective study that long-term outcome in MM patients was better with auto/RIC-allo as compared with auto-HSCT alone (Gahrton et al. , Blood 2013). The debate is still ongoing concerning the best time to propose allogeneic transplantation for MM patients; while there is agreement in the scientific community to perform it preferentially within a clinical trial, the majority of patients in Europe are still treated outside of a clinical trial. The objective of this study is to describe the context of use of allo-HSCT for MM in Europe within EBMT centers over more than two decades with the evaluation of different outcomes. Material and methods: We included in this study a total of 7333 patients who received allo-HSCT between January 1990 and December 2012, 4539 (62%) males and 2794 (38%) females with a median age at allo-HSCT of 51 years (range: 18-78), of which 4726 (64%) have been transplanted after year 2004. We identified 6 groups in this population, patients who received allo-HSCT upfront after induction therapy (Group 1, N=1934), patients who received allo-HSCT maximum 8 months after single auto-HSCT (Group 2, N=1997), patients who received allo-HSCT later than 8 months after single auto-HSCT (Group 3, N=1588), patients who received allo-HSCT maximum 8 months after double auto-HSCT (Group 4, N=588), patients who received allo-HSCT later than 8 months after double auto-HSCT (Group 5, N=930), and finally patients who received allo-HSCT after having received at least 3 different HSCT (Group 6, N=296). The different patient, disease and transplantation characteristics according to each group are detailed in the table. Results: The upfront use of allo-HSCT was seen to decrease after year 2000 to represent 12% of allo-HSCT performed in 2012 while the peak of allo-HSCT use directly after 1 auto-HSCT (within 8 months) was around year 2004 to attend 19% of usage in 2012. Remarkably, allo-HSCT was moreover used at the highest rate during the last years later than 8 months after single auto-HSCT which could be translated in a context of relapse post- first auto-HSCT to reach 33% of usage in 2012. The usage according to groups 4, 5 and 6 was 14%, 17% and 5% in 2012 respectively (Figure). The median overall survival (OS) for groups 1, 2, 3, 4, 5 and 6 was 33, 69, 25, 25, 23 and 15 months respectively with a 5 years OS probability of 39%, 53%, 33%, 31%, 29% and 23% respectively; the median progression-free survival (PFS) was 45, 39, 21, 22, 21 and 13 months respectively with a 5 years PFS probability of 43%, 42%, 26%, 28%, 24%, and 15% respectively. The cumulative incidence of transplant-related mortality for the 6 groups at 3 years was 36%, 20%, 32%, 33%, 36% and 35% respectively. The use of reduced intensity conditioning was associated with a significantly better OS only in group 2 compared to myeloablative conditioning with a median OS of 76 months versus 45 months (p=0.002) respectively. Year of transplantation before or after 2004 did not influence on outcomes. Conclusion: This large retrospective study shows different ways of using allo-HSCT for MM in Europe over a defined time period, it describes the different expected outcomes in each case. Allo-HSCT has not found its place yet in the treatment course of MM patients and the debate should continue based on advantages and disadvantages showed for each group of patients. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Introduction. Allogeneic stem cell transplantation (allo-SCT) is a well established therapeutic alternative for those patients with refractory Hodgkin’s lymphoma (HL) who relapse after an autologous stem cell transplantation (ASCT), have chemosensitive disease and a HLA compatible donor available. The impact of the intensity of the conditioning regimen in the outcome of this procedure is still not well understood. An initial retrospective analysis from the European Group for Blood and Marrow Transplantation (EBMT) Lymphoma Working Party (LWP) (Sureda et al, JCO 2010) that compared myeloablative (MAC) with reduced intensity conditioning (RIC) protocols indicated that the high non-relapse mortality (NRM) associated to MAC-SCT translated into a non-significant improvement in progression free survival (PFS) for RIC recipients in spite of the higher relapse rate of the latter. As NRM for MAC-SCT might have decreased over time due to better patient selection, HLA typing and peri-transplant supportive measures, we hypothesize that overall results of more intensive protocols could compare better to RIC-SCT in recent years. Patients and Methods. We have included in this analysis adult patients with multiply relapsed classical HL treated with an allo-SCT between January 2006 and December 2010 and reported to the EBMT Database. Only first and second allo-SCT was included. Tandem ASCT-allo-SCT was excluded as well as cord blood transplantations and haplo-identical SCT. A total of 313 patients met the inclusion criteria (63 patients treated with a MAC and 250 patients treated with a RIC, definitions following the EBMT criteria). There were 173 males (55%) and 140 females (45%) with a mean age at diagnosis of 29 years and at SCT of 33 years. Mean time from diagnosis to SCT was of 43.3 months. 153 patients (49%) were chemorefractory at the time of allo-SCT and 166 patients (53%) had already failed a prior ASCT. Peripheral blood (PB) was used as the source of stem cells in 88% of the patients. Comparing MAC with RIC groups, the latter one was significantly older at allo-SCT (31 years vs 34 years, p=0.01), had a longer time interval between diagnosis and allo-SCT and preferentially received mobilized PB stem cells (82% vs 91%, p=0.01). There were also more prior autograft failures in the RIC group (56% vs 42%, p=0.006). Results. With a median follow up for alive patients of 32.5 (9.7 – 52.9) months, overall survival (OS) was 75% and 65%, PFS, 54% and 39%, NRM 11% and 12% and relapse rate after SCT of 37% at 1 year. There were no significant differences in NRM between MAC and RIC patients. Relapse rate was higher in the RIC group, although these differences did not reach statistical significance (55% vs 40% at 24 months, p=0.1). This lower relapse rate translated into an improvement in PFS for the MAC group (48% vs 37% at 24 months, p=0.08) with no differences in terms of OS (71% for MAC vs 61% for RIC at 24 months, p=0.4). Multivariate analysis after adjusting for disease status at the time of SCT showed that the use of RIC protocols was the only independent adverse prognostic factor associated to a higher relapse rate after SCT [HR 0.68, 95%CI (0.38 – 0.98), p=0.04] and to a lower PFS after the procedure [HR 0.65, 95%CI (0.43 – 0.98), p=0.04]. The intensity of the conditioning regimen did not have any impact n NRM in the multivariate analysis. Chemosensitive disease at SCT was the only independent prognostic factor for OS after SCT in the multivariate analysis [HR 1.70, 95%CI (1.17 – 2.46), p=0.005]. Conclusions. This retrospective analysis shows that NRM after MAC protocols is not a significant clinical issue when allografting patients with HL nowadays. On the other hand, using MAC decreases the relapse risk in this highly resistant population of patients, translating into a significant improvement of PFS. MAC protocols should be considered when designing prospective clinical trials in patients with HL candidates for an allogeneic stem cell procedure. Disclosures No relevant conflicts of interest to declare.

Introduction Allogeneic stem cell transplantation is a curative and increasingly used treatment approach for a variety of hematological malignancies. Late complications such a chronic graft-versus-host disease (cGvHD) is a major risk factor, which significantly influences morbidity and mortality after allogeneic stem cell transplantation (ASCT). The incidence of cGvHD is higher when peripheral blood stem cells are used as stem cell source. There is a strong need for preventing cGvHD after ASCT without increasing the risk of relapse. Patients and Methods We performed a multicenter, multinational, open-label, randomized study comparing anti-lymphocyte globulin (ATG-Neovii®) 10mg/kg on day -3,-2 and -1 with no ATG in 155 patients with acute myeloid (n=110) or lymphoblastic leukemia (n=45) in 1st complete remission (CR; n= 139) or 2nd CR (n=16) who received peripheral blood stem cells from their HLA-identical sibling (n=148) or relatives (n=7) after standard TBI (12Gy)/Cyclophosphamide (120mg/kg) or Busulfan (16mg/kg)/Cy (120mg/kg) based myeloablative conditioning regimen and sufficient organ function. Standard GvHD prophylaxis consisted of cyclosporine A and a short course of MTX (10mg/m² on day +1,+3,+6 and +11). Major inclusion criteria were: acute myeloid or lymphoblastic leukemia in 1st or 2ndCR, age 18-65 years, HLA-identical sibling or relatives, peripheral blood stem cell as stem cell source, and a myeloablative conditioning regimen. The primary study aim was to compare the cumulative incidence of cGvHD at 2 years after ASCT. Results Out of 161 randomized patients from 27 centers and 4 nations, 6 were withdrawn before conditioning and ASCT due to leukemia progression, or cancellation of the donor. 155 patients were analyzed for safety and efficacy; 83 were randomized to ATG and 72 to non-ATG. The treatment groups were comparable regarding recipient and donor age and sex, CMV serostatus, disease (AML vs ALL), 1st or 2ndCR. The median time to leukocyte (>1.0x10e9/l) and platelet (> 20x 10e9/l) engraftment was significantly delayed in the ATG group (18 vs 15 days, p< 0.001 and 20 vs 13 days, p Conclusion This randomized cGvHD prevention study provides evidence that ATG-Neovii® 3x 10mg/kg within a myeloablative preparative conditioning regimen for HLA-identical sibling peripheral blood stem cell transplantation is highly effective in preventing limited and extensive cGvHD without obvious increase of infectious complications and relapse, resulting in similar overall survival rates. Disclosures Kröger: Neovii: Research Funding.

In the present study, we used a polymerase chain reaction–based (PCR-based) strategy to retrospectively analyze the presence of residual myeloma cells in serial posttransplant bone marrow samples obtained from 13 patients in remission after allogeneic hemopoietic stem cell transplantation (allo SCT). For this purpose, patient-specific primers were generated from complementarity determining regions 2 and 3 of the rearranged IgH gene. The level of sensitivity of the PCR-based assay ranged from 1 in 105 to 1 in 106 normal marrow cells. Following transplantation, 9 of 12 patients who attained stringently defined complete remission (CR) remained persistently PCR− for a median of 36 months, and 4 of the patients remained PCR− up to the latest analysis, which was performed at 48, 72, 72, and 120 months, respectively, after allo SCT. None of the patients in the PCR− subgroup experienced a disease relapse, and only 1 of 4 PCR+ patients experienced a relapse. It is concluded that allo SCT has the potential ability to induce sustained serological and molecular CR in selected patients with multiple myeloma.

Agnogenic myeloid metaplasia (AMM) is a chronic myeloproliferative disorder in which patients with poor prognostic features, receiving conventional treatments, have a median survival of less than 3 years. In this retrospective multicenter study, we analyze the results and try to define the indications for allogeneic stem cell transplantation in AMM. From January 1979 to November 1997, 55 patients with a median age of 42 years were transplanted from HLA-matched related (n = 49) or alternative (n = 6) donors for AMM. A multivariate analysis was conducted to identify factors associated with posttransplant outcome. The median posttransplant follow-up was 36 months (range, 6 to 223). The 5-year probability of survival was 47% +/- 8% for the overall group, and 54% +/- 8% for patients receiving an unmanipulated HLA-matched related transplant. The 1-year probability of transplant-related mortality was 27% +/- 6%. Hemoglobin level/=100 g/L and osteomyelosclerosis before transplant adversely affected the outcome. The probability of developing grade III-IV acute graft-versus-host disease (GVHD) was 33% +/- 8%. Sixteen of 45 patients developed extensive chronic GVHD. At last follow-up, 22 patients were in complete histohematologic remission. Treatment failure was observed in 13 cases. Age at transplant and karyotype were predictors of treatment failure. Allogeneic stem cell transplantation is an effective treatment leading to cure in a substantial number of patients with AMM. A better characterization of the variables affecting the posttransplant outcome should lead to a decreased transplant-related mortality and an improvement in these results.

To determine the incidence and outcome of hepatic veno-occlusive disease (VOD) after blood or marrow transplantation (BMT), we prospectively evaluated all consecutive patients receiving a BMT during a 6-month period in participating EBMT centers. All of them were evaluated for occurrence of VOD according to previously defined clinical criteria. The clinical course, outcome, value of prophylactic and therapeutic interventions, and the influence of previously described risk factors were analyzed. During the study period, 1,652 BMT were performed in 73 centers. VOD was diagnosed in 87 patients (5.3%; 95% confidence interval [CI], 4.2% to 6.4%). Fifty-six of 631 allogeneic BMT (8.9%) and 31 of 1,010 autologous BMT (3.1%) developed this complication (P.0001). VOD was classified as mild in 7 (8%), moderate in 56 (64.4%), and severe in 24 (27.6%) cases. Sixteen patients died of VOD (corresponding to 1% of the whole series, 18.4% of VOD patients, and 66.7% of severe VOD). The use of unfractionated heparin did not significantly decrease the incidence of VOD. Independent variables associated with an increased risk of VOD were allogeneic BMT (relative risk [RR], 2.8; P.001), pre-BMT elevation of serum aspartate aminotransferase (RR, 2.4; P =.001), high-dose cytoreductive therapy (RR, 2.3; P =.003), Karnofsky performance score less than 90% (RR, 2.7; P =.006), and prior abdominal radiation (RR, 2.9; P =.03). In conclusion, this prospective study shows that (1) the incidence of VOD is lower than that reported in smaller studies from single centers, (2) about one fourth of cases of VOD progress to severe disease, (3) main risk factors have a major impact on incidence of VOD, and (4) the use of prophylactic unfractionated heparin does not seem to reduce the incidence of VOD.

Introduction High-dose chemotherapy and autologous stem cell transplantation (ASCT) is a treatment option for eligible patients with systemic light chain (AL) amyloidosis. Compared to patients with multiple myeloma (MM), the risk for complications and transplant-related mortality is increased. However, in this fragile patient group it is often not possible to distinguish between treatment- and amyloidosis-related deaths in the post-transplant period. The CIBMTR reported a one year survival (1-yr OS) of 66% of patients transplanted between 1995 and 2001. Another multicenter analysis from Great Britain reported a one year survival of 75% (Goodman et al., BJH, 2006); interestingly, they could show a significant reduction of day 100 all-cause mortality from 32% to 13% after 1998. In recent single center studies 1-yr OS was better ranging from 80% to 90% (reviewed by Schönland et al., BMT, 2011). The amyloidosis groups of Mayo Clinic and Boston Medical School could also show a survival improvement over time (Tsai et al., Blood, 2012 and Gertz et al., BMT, 2010). Specific Aim The aim of this retrospective study was to analyze the 1-yr OS after ASCT for patients with AL amyloidosis in Europe. Of special interest were calendar year of transplants and center experience. Methodology Patient-, disease-, and transplant-related variables were collected according to the data entries in the EBMT database. Inclusion criteria were as follows: first autologous transplant with peripheral blood stem cells performed between 1997 and 2010. Center experience was measured for each patient by the number of previous MM ASCT done in the center until the year of AL transplant. Results 1315 patients from 259 centers fulfilled the entry criteria and were included in the analysis (for patient characteristics see table). The conditioning regimen was high-dose melphalan in most cases. Median follow up was 47 months. 1-yr OS after ASCT was 80.7% (CI 78.5 – 82.9). In univariate analysis age, gender, time from diagnosis to ASCT had no influence on 1-yr OS. Bad performance status (57% (50-65) vs. 90% (87-92); p Conclusion This is the first report from the EBMT about the results of ASCT in AL amyloidosis from 259 European centers and the largest retrospective analysis for this rare entity. It clearly shows that short term survival has been improved over time probably due to better patient selection and increase of center experience. Of note, in the most recent cohort (2009 to 2010) the 1-yr OS was 91% (CI 87-96) supporting the further use of ASCT in eligible AL amyloidosis patients. Disclosures: Leblond: Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Acute graft-versus-host disease (aGVHD) has been classified according to the Seattle criteria as grades 0, I, II, III, and IV for 20 years. The predictive value of such detailed grading is a matter of debate; publications usually report GVHD as present or absent or as absent, moderate, or severe. The Working Party Chronic Leukemia of the European Group for Bone Marrow Transplantation analyzed data of 1,294 patients transplanted from an allogeneic donor for chronic myelogenous leukemia (CML) in first chronic phase and tested the predictive value of aGVHD grading for the following end-points: day 100 mortality (D100M), transplant-related mortality (TRM), relapse incidence (RI), leukemia- free survival (LFS), and survival (SURV). aGVHD was absent in 462 patients (35.7%), grade I occurred in 335 (25.8%), grade II in 264 (20.5%), grade III in 110 (8.5%), and grade IV in 123 patients (9.5%). A total of 297 patients (23%) died within 100 days, 495 patients (38%) died of any TRM, and 100 patients (8%) died of relapse. D100M according to grades 0, I, II, III, and IV was 17%, 13%, 19%, 38%, and 70%, respectively, with significant difference between 0-II versus III-IV. TRM was 28%, 27%, 43%, 68%, and 92%, respectively, with a distinct separation between 0-I versus II-IV. RI showed a continuous decrease of 37%, 30%, 23%, 18%, and 8%, respectively, with increasing aGVHD. LFS was 45%, 51%, 44%, 26%, and 7%, respectively, and was best for patients with grade I aGVHD. This finding was also reflected in a better overall survival (60%, 64%, 53%, 30%, and 8%, respectively). The better LFS for grade I aGVHD patients compared with patients with grade 0 or II aGVHD was confirmed (P = .05) in a multivariate analysis. These data document the value of the present 5-point grading of aGVHD, ie, different outcome is observed depending on endpoint analyzed. Restricting information about aGVHD to presence or absence is not warranted.

Abstract 4287 Purpose: To evaluate safety, feasibility and anti-leukemia potential of haploidentical KIR-L mismatched natural killer (NK) cell infusion in elderly high risk acute myeloid leukemia (AML) patients. Patients and Methods: Thirteen patients (5 active disease, 2 molecular relapse and 6 complete remissions) with median age 62 years (range 53–73) received NK cell infusion after immunosuppressive chemotherapy (fludarabine/cyclophosphamide), followed by interleukin-2. Highly purified CD56+CD3- NK cells from haploidentical KIR-L mismatched donors were used. The median number of infused NK cells was 2.74 × 106/Kg. T cells were less than 105/Kg. NK cell chimerism, phenotyping, and functional assays were performed. Results: No significant toxicity, including graft versus host disease, related to NK cell infusion was observed. Among patients with active disease, 1/5 obtained transient complete remission (CR), whereas 4/5 patients had no clinical benefit. Both patients in molecular relapse obtained CR, which lasted 9 and 4 months. Three/6 patients in morphologic CR are disease-free after 34, 32 and 18 months. Donor NK cells were demonstrated in the peripheral blood (PB) of all evaluable patients with a peak at day 10 after infusion and, in some cases, also in the bone marrow (BM). NK alloreactivity was demonstrated in vivo by the detection of donor-derived postinfusion NK clones capable of killing recipient targets. Conclusion: Infusion of purified CD56+CD3- NK cells is feasible and safe in elderly high risk AML patients. Adoptively transferred NK cells, which can be detected in PB and BM after infusion, are alloreactive against recipient cells and may induce an anti-leukemic activity. Disclosures: No relevant conflicts of interest to declare.