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Background: Anticomplement C5 therapy with eculizumab is the standard of treatment of patients (pts) with active hemolytic PNH. However, there are few data on long-term complement inhibition efficacy and current PNH prognosis from real-world clinical practice. Objectives: The aim of this study was to evaluate long-term eculizumab efficacy and PNH outcomes in the large cohort in Russia. Methods: As of August 1, 2018, a total of 354 pts with hemolytic PNH were observed in the I.P. Pavlov First St. Petersburg State Medical University in cooperation with the local hematological service in 75 regions of Russia (n=344), as well as in Belarus, Kazakhstan, Kyrgyzstan, Ukraine, Tajikistan (n=10) (Table 1). The analysis was conducted in the whole cohort and separately in the prospective phase after November 2011 with the eculizumab availability in Russia. We analyzed indications and access to anticomplement C5 therapy according to National guidelines (2014), frequency and causes of discontinuation of therapy, cumulative incidence of independence from transfusions with allo-HSCT as competing risk, frequency of breakthrough hemolysis (BTH) and intensive extravascular hemolysis, overall survival (OS) and causes of mortality. Results: According to the current National guidelines (2014), 323 pts had at least one indication for therapy with eculizumab: thrombosis (n=89, 25 %), transfusion-dependent hemolytic anemia (n=261, 74 %), acute kidney injury (AKI, n=69, 19 %), chronic kidney disease (CKD, n=244/304, 80 %) including CKD stage ≥ 2 (n=66/304, 22 %), pulmonary hypertension (n=66/265, 25 %) and pregnancy (n=22). Due to differences in regional support for rare diseases, only 204 (63%) pts had access to therapy with eculizumab. In addition, 19 pts received novel anti-C5 agent in clinical trial and were excluded from analysis. Allogeneic HSCT was performed in 24 pts, including 2 cases of MDS/AML evolved from AA/PNH and 17 cases of severe AA/PNH with eculizumab bridging in the prospective phase. With the median duration of eculizumab therapy of 3.4 years (0.2-6.1) the independence from RBC transfusions (TI) was achieved in 109 of 154 initially transfused pts (71 %) with a cumulative incidence of 61 % (95 % CI, 52-68) and 69 % (95 % CI, 60-76) after 12 and 24 months of therapy respectively. The median hemoglobin level at last follow-up were 6.6 (4.0-9.7), 10.5 (range, 7.1-15.4) and 12.1 g/dl (8.9-14.0) in patients who did not reach the TI, who reached the TI and were never transfused, respectively (p =0.0001). BTH was documented in 36 of 184 evaluated pts (20 %), including 16 and 20 cases with and without obvious triggers respectively. Intensive extravascular hemolysis with bilirubin level > 2xULN persisted in 31 % pts. Temporary or permanent discontinuation of eculizumab treatment occurred in 58 pts due to death (n=11), allogeneic BMT (n=17), spontaneous clone reduction (n = 4), absence of new indications 6 months after delivery (n=4), and terminating access to treatment (n=22). All pts of the latter group developed a relapse of intensive intravascular hemolysis, which in 3 cases was complicated by AKI (n=1), stroke (n=1) and myocardial infarction (n=1). OS was assessed in the prospective phase after 2011. A total of 24/203 (12 %) pts died which resulted in 5-year OS of 87% (CI 95 %, 81-92). Treatment with eculizumab significantly improved OS (Fig.1). The 5-year OS rate was 91% (CI 95 %, 85-98) in pts treated with eculizumab and 74 % (CI 95 %, 63-85) in never-treated pts (p=0.0003). There were significant differences in the causes of death between pts receiving and not receiving eculizumab: related to thrombosis 1/7 (14 %) vs 9/17 (53 %), AA and MDS 4/7 (57%) vs 5/17 (29 %). Conclusions: The results of the study show both the high efficacy and limitations of treatment with eculizumab for PNH in real-world practice. Prospectively confirmed significant improvement of the overall survival on eculizumab stress the need for faster and wider access to costly therapy. Nevertherless, a number of limitations, including BTH and extravascular hemolysis, lack of control of bone marrow failure and further clonal evolution, determine the relevance of next-generation complement inhibitors and risk-adjusted allogeneic HSCT as a curative option. Disclosures Kulagin: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria.

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SummaryTransplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of "novel" schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk.The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes. PATIENTS AND METHoDS97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4. RESULTSCumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and PtCy-based GVHD prophylaxis.

Background. In the expanding population of immunocompromised patients rare fungi have emerged as important pathogens, causing invasive infections associated with high morbidity and mortality. The number of publications on the invasive fungal diseases caused by rare pathogens (rare IFD) after hematopoietic stem cell transplantation (HSCT) and chemotherapy is limited. Patients and methods. We design the retrospective study in order to investigate the epidemiology of rare IFD in large cohort of patients after HSCT and chemotherapy for 11-year period. From 2008 to 2018 in R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation (CIC725) were performed 3209 HSCT including 2118 allogeneic (allo-HSCT) and 1037 autologous HSCT (auto-HSCT). During the observation period 41 probable and proven rare IFD (EORTC/MSG 2008 criteria) cases were diagnosed in children and adults with hematological malignances and non-malignant hematological diseases after allo-HSCT (n=30), auto-HSCT (n=2), and chemotherapy (n=9). The median age was 24 (2-59) y.o., males - 61%(n=25). The median follow up time for rare IFD cases was 3 months; for survivors - 30 months. Results. Incidence of rare IFD in HSCT recipients was 1,3%, it was higher after allo-HSCT (1,4%) than auto-HSCT (0,2%) (p<0,002). In nine patients, this complication developed after CT and four of them proceed to allo-HSCT. The most frequent underlying diseases were acute lymphoblastic leukemia (32%) and acute myeloid leukemia (29%). The median time of onset of rare IFD after allo-HSCT was 104 (21-1057) days, auto-HSCT - 138 (60-216), after start of CT - 161 (79-189). Etiology of rare IFD was identified by culture in 61% cases: Rhizopus spp. - 44%, Paecilomyces spp. - 16%, Fuzarium spp. - 8%, Malassezia furfur - 8%, Trichosporon asahii - 4%, Scedosporium apiosperium - 4%, Scopulariopsis gracilis - 4%, Rhizomucor pusillus - 4%, mix rare IFD with Rhizopus spp. + Paecilomyces spp. - 4%, Paecilomyces spp. + Fuzarium spp. - 4%. 35% cases (mucormycosis) were diagnosed with microscopy. In 44% cases rare IFD developed after or in combination with invasive aspergillosis, and 2 patients had both preexisting invasive aspergillosis and co-infection with mucormycosis. The main site of infection were lungs (82%), the main clinical symptom - fever (95%). All patients were treated with antifungals: lipid amphotericin B - 32%, lipid amphotericin B + caspofungin - 23%, voriconazole - 15%, posaconazole - 12,5%, lipid amphotericin B + posaconazole - 10%, and echinocandins - 7,5%. Surgery was used in 10% patients. Overall survival at 12 weeks from the diagnosis of rare IFD was 51,2%. The 12-weeks overall survival was better in patients after CT and auto-HSCT (81%) than allo-HSCT (40%), p=0,025. Conclusions. The incidence of rare IFD in HSCT recipients was 1,3% and depends on type of transplantation. Rare IFD was a late complication after chemotherapy and HSCT and usually developed after or in combination with invasive aspergillosis. Higher incidence and worst prognosis of rare IFD was observed in allo-HSCT recipients. Disclosures Moiseev: MSD: Other: Travel grants; Pfizer: Other: Travel grants; Celgene: Consultancy, Other: Travel grants; BMS: Other: Travel grants; Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; Takeda: Other: Travel grants.

Background: Relapse of ALL remains the major cause of transplant failure. Relapse incidence after allo-HSCT is described in 30-40% of patients. Patients with ALL receive allo-HSCT with MAC more often because after RIC more relapses are expected. The aim: To compare the frequency of relapse after allo-HSCT with RIC vs with MAC and to analyze the factors influencing the risk of relapse depending on the intensity of conditioning regimens. Patients and methods: Between 12/2000 and 09/2019 at RM Gorbacheva Research Institute a total of 235 children with ALL (median age of 10 years (0,5-18), underwent allo-HSCT. MAC (busulfan- or treosulfan-based) were used in 163 pts: 1st CR - 30 pts (MRD+ n=13), 2nd CR - 58 pts, 3rd or 4 CR - 27 pts, relapse - 48 pts. Allo-HSCT with RIC were performed in 72 pts: 1st CR - 12 pts (MRD+ n=9), 2nd CR - 29 pts, 3rd or 4 CR - 14 pts, relapse -17 pts. RIC consisted of fludarabine (30 mg/m2/d x 5 days) + melphalan (70 mg/m2/d x 2 days) or fludarabine (30 mg/m2/d x 5 days) + busulfan (4 mg/kg/d x 2 days). Matched related allo-HSCT was performed in 37 pts (16%), matched unrelated - in 128 pts (54%), haploidentical-in 70 pts (30%). Cumulative incidence functions were used to estimate relapse incidence and NRM in a competing risk setting. Univariate analyses were performed using Grey test for cumulative incidences. Multivariate analyses were performed using the Cox proportional-hazard model. Results: Median follow-up was 5,4 and 4,5 years for МАС and RIC, respectively. Relapses were diagnosed in 105 pts (44%) during 1-39 months after allo-HSCT (median 7.5 months) (90% relapses were during first 18 mo), 74 pts after MAC; 31 pts after RIC (p=0,549). Relapses occurred significantly less frequent (p=0,007) in patients who had CR at the moment of allo-HSCT - 61 pts (35%) (RIC -32%; MAC -37%) compared patients who had a relapse or primary resistance 44 pts (68%) (RIC-74%; MAC - 65%). The risk of relapse after MAC is influenced by the presence of acute GVHD (p=0,007), the source of HSCs (PBSC vs BM, p=0,032), and the status of the disease (CR vs relapse) at the moment of allo-HSCT (p=0,001). The risk of relapse after RIC is influenced by the presence of acute GVHD (p=0,042), age at the moment of allo-HSCT 1-10 years (p=0,032), and the status of the disease (CR vs relapse) at the moment of allo-HSCT (p=0,001). Multivariable analysis confirmed a significant impact of disease status at the moment of allo-HSCT whit MAC (p=0,001) and with RIC (p=0,002). Presence of aGVHD was additional factor associated with lower relapse risk in multivariate analysis in pts after MAC (p=0,005). Patients with active disease at the moment of HSCT had higher relapse-free survival after RIC (RIC-23% vs MAC- 12%, p=0,012). Salvage patients in whom the relapse was documented after HSCT had 28% and 38% probability of long-term OS after RIC and MAC, respectively (p=0,572). Conclusion: Relapse incidence after allo-HSCT with MAC and with RIC is comparable. The most significant factor affecting the risk of relapse is the status of the disease at the moment of allo-HSCT. Disclosures No relevant conflicts of interest to declare.

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Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1–18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0–181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course.