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Patients with hematological malignancies (HM) undergoing hematopoietic stem cell transplantation (HSCT) have an increased vulnerability to SARS-Cov-2 (Sharma et al, Lancet Haematology 2020; Ljungman et al, Leukemia 2021), the reason why international guidelines strongly support the need for a protective vaccination for these subjects. The most relevant data currently available on the response to a complete anti-SARS-Cov-2 vaccination cycle in HM patients after HSCT refer to 314 patients reported in a Lithuanian national survey (Maneikis et al, Lancet Haematol 2021). In this study, the median titers of antibodies against SARS-Cov-2, determined 7-21 days after the second vaccination, were comparable to that of healthy controls (HC) in both autologous and allogeneic groups, with no patient found below the protective threshold of 50 arbitrary units (AU)/ml. Notably, the large majority of patients had received the transplant more than 1 year before vaccination. In a prospective, cohort study, we compared 114 patients, who had received an autologous or allogeneic HSCT at least three months before the first dose of vaccination, to 107 HC, matched for age and sex. Study population and HC received two doses of BNT162b2 anti-SARS-Cov-2 mRNA vaccine on days 1 and 21, between April and May 2021. Serological tests were performed by a commercially available immunoassay for the quantitative determination of anti-spike IgG antibodies to SARS-Cov-2. The cut-off for defining responders was 50 or greater AU/ml. Patients and HC samples were collected four weeks after the second dose of the vaccine. Table 1 reports the main clinical characteristics of patients and HC. Eighteen of 114 patients (16%) did not respond (24% in the allogeneic group, 6% in autologous recipients). Overall, median antibodies titers did not differ between HC and the entire cohort of transplanted patients, recipients of allogeneic HSCT, all patients responding to the vaccine or responders in the autologous subgroup (Figure 1A). All autologous HSCT recipients had significantly lower titers of antibodies than HC, while higher levels were found in responders who had received allogeneic HSCT (Figure 1A). Responders in the allogeneic subgroup showed antibodies titers significantly higher than responders in the autologous subgroup (Figure 1B). We further stratified patients in three groups, according to the time elapsed from transplant to vaccination: G1:5 years. Higher antibodies titers were observed in HC compared to all transplanted patients in G1 (Figure 1C), including both allogeneic (Figure 1D) and autologous (Figure 1E) HSCT recipients. No differences emerged in G2 between HC and all patients (Figure 1C), allogeneic (Figure 1D) or autologous (Figure 1E) HSCT recipients. Finally, no differences were found in G3 when comparing HC with all patients (Figure 1C) or allogeneic recipients (Figure 1D), whereas patients in the autologous subgroup showed significantly lower titers than HC (Figure 1E). Myeloma patients with controlled disease showed higher titers than patients with active disease (Figure 1F). According to median age, autologous HSCT recipients older than 57 years had significantly lower antibody levels than younger patients (Figure 1G). Autologous vs allogeneic HSCT, age of all patients and of allogeneic HSCT recipients, sex, type of allogeneic HSCT, conditioning regimen, age and sex of donor, occurrence of GVHD, disease type and single vs double autologous HSCT did not significantly impact on antibody levels (data not shown). No relevant side effects were recorded after vaccination. With a median follow up of 12 weeks, no case of COVID19 occurred among vaccinated patients. In our single center study, patients with a previous history of HSCT tolerated well BNT162b2 vaccine and mounted a potentially protective immune response in the majority of cases one month after two doses of vaccine. However, lack of response was not rare, especially in the allogeneic setting. The main factor associated with the quality of response was the time from HSCT, with lower responses within the first year from transplant and differences between autologous and allogeneic groups transplanted more than five years before vaccination. Here, a consolidated, complete immune reconstitution in allogeneic HSCT recipients, as well as age and a still active disease in the autologous setting, could have played opposite pivotal roles. Figure 1 Figure 1. Disclosures Delia: Gilead: Consultancy; Amgen: Consultancy; abbvie: Consultancy; Jazz pharmaceuticals: Consultancy.

Introduction: Bosutinib is a Src/Abl tyrosine kinase inhibitor (TKI) currently licensed for patients with Ph+ chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) Chronic Myeloid Leukemia after failure or intolerance to at least 2 other TKIs. It can also be prescribed, in accordance with label if, after failure of the first TKI therapy, another option does not seem feasible. Previous studies demonstrated a potent activity of second-line bosutinib across a spectrum of BCR-ABL1 mutations and a distinct toxicity profile compared to other TKIs. Aim: We retrospectively assessed the efficacy and safety of real life Bosutinib administration in 85 patients resistant/refractory or intolerant to other TKIs, referred to 22 Italian Hematological Institutions. The main features at Bosutinib start are reported in the Table. Results: At Bosutinib start, all patients were in CP. 60 patients (71%) were resistant/refractory, 25 (29%) were intolerant to previous TKIs. BCR-ABL1 kinase mutations were reported in 5/35 evaluable patients (14%); no T315I was reported. The number of previous TKIs was less than 3 in 24/85 patients (28%) and 3 or more in 61 (72%). Comorbidities were present in 63 patients (74%), the most common being arterial hypertension (40), diabetes (14), cardiac disease (10) and chronic obstructive pulmonary disease (6). The most frequent concomitant medications were: antihypertensive in 55% patients, antiplatelets in 26%, antidiabetic in 19%. The initial dose was 100 mg in 4/85 patients (5%), 200 mg in 24 (28%), 300 mg in 18 (22%), 400 in 8 (9%); 31 patients (36%) started at the full standard dose of 500 mg. Major Molecular Response (MMR)/Deep Molecular Response (DMR) were achieved by 37/80 (46%) evaluable patients; 43/80 patients (54%) never reached a MMR/DMR at any time. Best responses in these cases were: Complete Hematologic Response (CHR) in 4 patients (9%), Partial Cytogenetic Response (PCyR) in 6 (14%), Complete Cytogenetic Response (CCyR) in 10 (23%). Dose reductions were necessary in 4 patients (5%) due to adverse events (2 cases of diarrhea, 1 transaminase elevation, 1 skin rash). After a median follow-up of 26 months (range 3-49), 75/85 patients (88%) are alive and 54/75 patients (72%) are still in treatment. Discontinuations were due to: intolerance in 8/75 patients (11%), loss of response in 3/75 (4%), resistance to therapy in 10/75 (13%). Hematological toxicity was observed in 14 patients (16%), any grade, and grade 3-4 in 3 (3%). Extra-hematological toxicity was reported in 41/85 patients (48%), any grade, and grade 3-4 in 14 patients (16%). Causes of death were: acute myocardial infarction (3), cardiac failure (2), acute respiratory distress (2), allogeneic transplant complications (1), cerebral hemorrhage (2). Conclusions: In our "real life experience" with Bosutinib, we confirm a stable long-term efficacy in heavily pre-treated, mainly elderly patients with intolerance/resistance to other TKIs, who show an initial response to treatment, as reported in clinical trials. Patients show a fast response to the drug (mainly at three months). Hematological and extrahematological toxicities are manageable. Disclosures Breccia: BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Abruzzese:Novartis: Consultancy; Ariad: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Castagnetti:Bristol Meyers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bonifacio:Novartis: Research Funding; Amgen: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Bristol Myers Squibb: Consultancy.

Up to 40% of patients with myelodysplastic syndromes (MDS) respond to pharmacological doses of epoetin. Darbepoetin alfa (DPO) has a longer half-life and greater biological activity. Recent data suggest a 60% response rate in patients receiving DPO. We report preliminary results of a Phase II study in 41 patients with low and intermediate-1 risk MDS and Hb < 11 g/dL. The primary endpoint is to evaluate the efficacy of DPO for the treatment of anemia of MDS. Secondary endpoints are the evaluation of the safety of DPO and of the variations in Hb, the number of monthly transfusions and quality of life (QoL) in treated patients. Patients receive DPO 150 mcg s.c weekly to be doubled in non-responders. Treatment target is Hb =12.0 g/dL. Treatment is to be temporarily interrupted for Hb >12 g/dL and re-initiated when Hb Results: The 33 patients who received at least 8 weeks of DPO included 19M/14F of median age 74 (range 49–84) years. Morphology was: 31 RA, 1 RARS and 1 CMML. IPSS score was low in 75%, and Int-1 in 25%. Serum epoetin levels were < 200 mU/ml. Meduab Hb level at baseline was 9.5 (range 7.0–10.8) g/dL. Six patients had previously received epoetin alfa or beta without success. Thirteen patients (39%) were transfusion-dependent. At the initial dosage, 6 transfusion-free patients (30%) responded at 4 weeks (3 reached the endpoint of Hb=12.0 g/dL). Total number of cases responding at 8 weeks were 17, including 7 (53%) transfusion-dependent patients. Ten responses were minor (30%) and 7 major (21%). After dosage doubling, there were 56% responders of the 16 patients that have completed the study at 24 weeks: 7 of 12 transfusion-free patients (2 at a dosage of 150 mcg/wk, 2 at 300 mcg/wk and 3 at 300 mcg every 3 weeks) and 2 of 4 transfusion-dependent patients at a dosage of 300 mcg/wk. Five patients reached Hb > 12g/dl during the study period. Finally, 3 of the 6 patients previously unresponsive to epoetin responded to DPO. At univariate ANOVA analysis, response to treatment was associated with increases in QOL-E treatment outcome index (p=0.033), specific (p=0.009), fatigue (p= 0.013), physical (p=0.001), functional (p=0.042), social (0.001), general (p=0.001), and total (p=0.004) scores. There were significant reductions in CD34+ cells (p=0.025) and apoptotic cells (p=0.008) and these were associated with treatment response (p=0.045 and p=0.065, respectively). No adverse events were reported. Conclusions: DPO is safe and well-tolerated in patients with MDS. A reduction in apoptotic cells is observed during treatment. Therapeutic response is associated with improvements in QoL. Our study suggests that DPO is effective for the treatment of anemia of MDS.