ALBERT

Description: Background. Chromosomal abnormalities (CA) are the most prognostic factor in acute myeloid leukemia (AML). However, it is still not clear whether the cytogenetic risk groups established for patients (pts), treated by standard chemotherapy, are so optimal for pts undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Recent studies have confirmed negative effects of both monosomal and complex karyotypes (MK, CK) on outcomes after alloHSCT [1,2]. Meantime, some investigators consider that immune effects of alloHSCT can reduce negative impact of these CA [3]. Aim. To evaluate impact of the CA in AML pts with adverse cytogenetic risk group on outcome after alloHSCT. Material and Methods. In this study, outcomes of alloHSCT, which were performed in a single institution between 2009 and 2014 years for 97 AML pts have been analyzed. Patients and transplantation characteristics are presented in Table I. The probabilities of overall survival (OS), leukemia free survival (LFS), cumulative incidence of relapse (CIR) were evaluated for different cytogenetic groups. Results. According to univariateanalysis, the probabilities of 4-year OS in pts with 5q-, KMT2A translocations and monosomy 7 were 66%, 59% and 56%, respectively. At the same time, OS in pts with CK, 7q- and 3q26 rearrangements were lower i.e. 33%, 25% and 25%, respectively (p=0.01). Multivariate analysis showed, that clinical stage at HSCT, age and HSC source are independent predictors of OS in AML pts (Table 2). Four-year LFS were various in pts with different CA. The higher LFS was noted in pts with 5q- and KMT2A translocations (66% and 52%, respectively), whereas lower LFS were in pts with 3q26 rearrangements, CK, monosomy 7 and 7q- (0, 18%, 23% and 37%, respectively) (Fig. 1). Besides, LFS distinguished between groups with CK+ and CK- (18% vs 41%, p=0.008), as well as with MK+ and MK- (17% vs 30%, p=0.04). Multivariate analysis evidenced clinical stage at HSCT, cytogenetic groups, MK and number of transplanted CD34+ cells to be independent predictor of LFS in AML pts (Table 2).Cumulative incidence of relapses in pts transplanted in remission (n=42) was higher in those with CK+ (55% vs 14%, p=0.03) and MK+ (75% vs 31%, p=0.013). Discussion. The study showed that 4-year OS in AML pts with 5q-, KMT2A translocations and monosomy 7 significantly distinguished from those with CK, 7q- and 3q26 rearrangements. Furthermore, OS depended on clinical stage at HSCT, patient's age and HSC source. On the other hand, EFS differed from all above-mentioned cytogenetic groups, including MK. Finally EFS depended on clinical stage at HSCT and number of transplanted CD34+ cells. Conclusion. On the basis of this data, a conclusion may be drawn that alloHSCT in AML pts with adverse CA should be performed at complete remission, with bone marrow as HSC source and enough number of transplanted CD34+ cells. Reference. 1. Hemmatti et al. Eur J Haematol. 2013; 92:102-10. 2. Fang et al. Blood 2011; 118:1490-4. 3. Guo et al. Biol Blood Marrow Transplant 2014; 20: 690-5. Table 1. Patients and Transplant characteristics Patients, n (%) 97 (100) Gender, n (%)MaleFemale 53 (54.6)44 (45.4) Age at HSCT, median, (range) years 25 (1.5-60) Cytogenetics, n (%) 3q26 rearrangementsDeletion 5q (sole)Monosomy 7 (sole)Deletion 7q (sole)KMT2A translocationComplex karyotype ³3 CA Monosomal karyotype 4 (4)10 (10.3)12 (12.4)4 (4)11 (11.3)56 (58)18 (18.5) Time from diagnosis to HSCT, median (range) days 477 (47 - 3482) Clinical stage at HSCT, n (%)CR1³CR2Active disease 29 (30)13 (13)55 (57) HSC source, n (%)Bone marrowPeripheral bloodBM+PB 54 (56)34 (35)9 (9) Conditioning regimen, n (%)MANon-MA 35 (36)62 (64) Donor type, n (%)HLA-id siblingMatched unrelatedHaploidentical 17 (17.5)53 (54.6)27 (27.8) Number of transplanted CD34+ cellsmedian (range), x106/kg 6.1 (1.5-17.9) Table 2. Multivariate analyses HR 95% CI P Overall survival Clinical stage at HSCT 2.65 1.72-4.09 0.00001 Median age6x106/kg 1.77 0.91-3.42 0.08 Leukemia-free survival Clinical stage at HSCT 2.59 1.8-3.7 0.0001 Cytogeneticgroups 1.31 1.03-1.69 0.031 Monosomal karyotype 1.88 0.97-3.66 0.044 Median number of transplanted CD34+ cells〉6x106/kg 2.78 1.51-5.11 0.0003 Figure 1. Leukemia-free survival for AML patients with different cytogenetic groups after alloHSCT Figure 1. Leukemia-free survival for AML patients with different cytogenetic groups after alloHSCT Disclosures No relevant conflicts of interest to declare.

Description: Background. Prognosis of acute myeloid leukemia (AML) with complex aberrant karyotype (CAK) is poor. These patients (pts) are often refractory to both chemotherapy and allogeneic HSCT (alloHSCT). At diagnosis the proportion of these pts is about 6-8 %, but their frequency essentially increases in relapses after chemotherapy and alloHSCT. Mechanism of CAK development and its effect on relapses have been studied insufficiently. Material and methods. Serial cytogenetic assays, including multicolor FISH, were performed on bone marrow cells from 99 patients with post-transplant relapses (PTR) AML (n=61) and ALL (n=38). Median ages for AML and ALL pts at HSCT were 23 and 17 years (range, 2-60 and 0.8-51 years), respectively. Results. Aberrant karyotypes were found in 90 % AML and 97 % ALL pts, respectively (Table 1). Of note, the proportion of CAK in general group of ALL patients, as well as in that with more 4 chromosomal abnormalities was significantly higher, compared to AML (66% vs. 36%, P=0.003 and 61% vs. 33%, P=0.006, respectively). Table 1. Frequency and characteristics CAKs in AML and ALL patients with the PTRs Leukemia type AML ALL P Patients, n 61 38 Karyotype, n (%) Normal 6 (10 %) 1 (3 %) NS Abnormal 55 (90 %) 37 (97 %) NS Complex karyotype, n (%) 22 (36 %) 25 (66 %) 0.003 3 abnormalities 2 (3 %) 2 (5 %) NS ³4 abnormalities 20 (33 %) 23 (61%) 0.006 NS - not significant The above difference in frequency of CAK in ALL and AML might be explained by higher frequency of myeloablative conditioning regimes in the ALL group, compared to AML (55% vs. 36 %, respectively; P=0.09). Of notice also, that fraction of CAK with 4 and more chromosomal abnormality in the group of children from 1 to 18 years was significantly higher in patients with ALL, as compared with AML (60% vs. 30%, respectively; P=0.03). Furthermore, a similar tendency was revealed also in the group of patients aged 19-40 years (difference insignificant; P=0.08) (Table 2). Table 2. The incidence of CAKs with ³4 chromosomal abnormalities in PTRs in different age groups. Patients, n (%) Age (years) AML ALL P 1-18 7/23 (30 %) 15/25 (60 %) 0.03 19-40 8/25 (32 %) 7/11 (64 %) 0.08 41-60 5/13 (39 %) 1/2 (50 %) 0.5 Finally, our data demonstrate, the proportion of CAK to be significantly higher in PTR of ALL pts compared with those of AML, when they were transplanted in active disease phase (70% vs. 32%; P=0.007; Table 3). Table 3. The incidence of CAKs with ³4 chromosomal abnormalities in PTRs, depending on the clinical status at alloHSCT. Patients, n (%) P Clinical status at HSCT AML ALL CR 1 3/13 (23 %) 2/7 (29 %) 0.6 CR ³2 6/14 (43 %) 7/11 (64 %) 0.2 Active disease 11/34 (32 %) 14/20 (70 %) 0.007 Discussion. Our study shows that number of karyotype abnormalities in acute leukemia with CAK+ is closely associated with previous chemotherapy and/or conditioning regimes. Despite it, only alloHSCT gives a hope for treatment of these pts. In order to improve overall results of treatment several modifications of alloHSCT and post-transplant treatment have been recently suggested. The main of them, called as early alloHSCT, includes modified FLAMSA-RIC conditioning regime, alloHSCT before obtaining results of standard courses chemotherapy followed by DLI in escalating doses at post-transplant period (Schmid et al., 2012). If such a possibility for early alloHSCT is lost, another variant of PTR prevention may be used. The latter can include the same DLI, hypomethylating agents, ATRA etc. As for PTR prevention in CAK+ ALL it may be different from AML. In our opinion, in these pts should be treated at the first with such target agents as tyrosine-kinase inhibitors, rituximab, ATRA etc. Conclusion. According to our data, the frequency of CAK in PTRs is high not only in AML, but ALL too. Mechanisms of CAK formation as well as treatment of CAK+ leukemia began to elucidate. In our opinion, the leading place in this treatment is to be given an early alloHSCT. Reference. Schmid C., et al. Early allo-SCT for AML with a complex aberrant karyotype – results from prospective pilot study. Bone Marrow Transplantation 2012; 47: 46-53. Disclosures No relevant conflicts of interest to declare.

Description: Background There was a limited improvement in the results of allogeneic hematopoietic stem cell transplantation (HSCT) in refractory leukemia over the last decades. The major reason of poor results is the relapse of the underlying malignancy. Thus the technologies to augment graft-versus-leukemia (GVL) effect is required for this group of patients. The preclinical study by Stokes et al. (British Journal of Haematology, 2016) indicated prolonged survival in the leukemia mouse model with substitution of posttransplantation cyclophosphamide (PTCy) with bendamustine (PTBenda). Also a small study evaluated the combination of PTCy and PTBenda in young patients and children (Katsanis E et al., 2018). We conducted the prospective study of postransplantation bendamustine as graft-versus-host-disease prophylaxis. Methods Single-center prospective dose-ranging de-escalation study (NCT02799147) evaluated safety and efficacy of PTBenda as GVHD prophylaxis. PTbenda was administered in doses 140, 100 and 70 mg/kg on days +3,+4. Myeloablative conditioning with fludarabine and busulfan was performed. First patients enrolled received single-agent PTbenda and subsequent- combination with other immunosuppressive agents. Inclusion criteria were acute myeloblstic (AML) or lymphoblstic leukemia (ALL) refractory to at least one induction course of chemotherapy or target therapy and more than 5% clonal blasts in the bone marrow. Twenty three patients were enrolled, 7 in the 140 mg/kg cohort, 10 in 100 mg/kg and 6 in 70 mg/kg, including 18 with AML and 5 with ALL. 35% of patients had primary refractory disease, and the rest - second or subsequent relapses, 61% had high-risk cytogenetics, 35% - complex karyotype, 17% - secondary AML, 30% - extramedulary disease. Median number of induction courses was 2 and 39% received target antibodies. Median number of blasts at transplant was 18% (range 6-97%). Two patients had matched related donor (MRD), 15 - unrelated (MUD), 6- haploidentical. Results Median follow-up was 10 months. The 140 mg/kg cohort was closed prematurely due to severe infectious complications. Ninety one percent of patients engrafted. Median time to engraftment was 16 days. Among the engrafted patients CR rate was 95%, and 67% had MRD(-) status. Relapse was documented in 10% of patients with CR. We have observed that PTBena induces a specific cytokine-release syndrome (CRC) with fever, vasculitis-like skin rush, oral mucositis, enteritis, hepatitis and pancreatitis. CNS signs, hypotension and respiratory failure were observed only in a few patients. CRC was observed in 78% of patients, including grade 1-2 in 17%, grade 3 in 26%, grade 4 in 22% and grade 5 in 3 patients. Median level of ferritin during CRC was 15 000 ng/ml and IL-6 levels were also increased (74 vs 8 ng/ml, p=0.036). Tocilizumab was administered to 13 patients and 10 responded. Classical grade II-IV GVHD was observed in 39% of pts and 60% of long-term survivors developed severe chronic GVHD. Non-relapse mortality was 48% with CRC, infectious complications and chronic GVHD as major causes. 1-year overall survival was 35%. Conclusion PTbenda even as a single agent has a significant potential to prevent acute, but not chronic GVHD. Moreover GVHD prophylaxis with PTbenda is a completely novel approach to induction of GVL, but optimal combination of immunosuppressive agents and supportive care should be determined to control the CRC and chronic GVHD. The optimal dosing regimen of PTbenda will be determined after enrollment in the last cohort will be completed. Figure Disclosures Moiseev: Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; MSD: Other: Travel grants; Celgene: Consultancy, Other: Travel grants; BMS: Other: Travel grants; Takeda: Other: Travel grants; Pfizer: Other: Travel grants. OffLabel Disclosure: Bendamustine used for graft-versus-host disease prophylaxis.

Description: Background. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). The conditioning regimen administered for this patient based on busulfan combined with cyclophosphamide (BuCy), fludarabine (BuFlu) or some other agents. Comparisons of myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) have demonstrated a various results between relapse and toxicity in a few reports. We supposed, that dose intensity of busulfan across regimens may affect treatment outcomes. The goal of this retrospective study was to evaluate the impact dose of busulfan to overall survival (OS), transplant-related mortality (TRM), relapse-free survival (RFS), toxicity, the incidence of primary graft failure and acute graft-versus-host disease (GVHD) in transplantation in children and adolescents with AML. Material and methods. We analyzed 110 AML pediatric patients with the median age 9 y.o. (range 1-19), who underwent first allo-HSCT with busulfan based (per os and IV) conditioning in R.M. Gorbacheva Memorial Institute from 2002 to 2018. Patients were divided into 3 groups: Bu1 - patients, who received busulfan at the dose 8-10 mg/kg, n=34 (31%), in Bu2 - dose of busulfan was 12 mg/kg, n= 35 (32%), in Bu3 - dose of busulfan was 〉12 mg/kg, n= 41 (37%). In Bu1 busulfan was combined with Flu in 31 pts (91%) and Cy in 3 (9%); in Bu2 - with Flu in 12 (34%) , Cy in 7 (20%) and other agents in 16 (46%); in Bu3 - with Cy in 32 (78%), with Flu in 7 (17%) and other agents in 2 pts (5%) (p 〈 0.001). Patients in Bu2 received more Cy based GVHD prophylaxis regimens (69% vs 44% in Bu1, vs 29% in Bu3, p = 0.003) and more HAPLO grafts (51% vs 29% in Bu1, vs 15% in Bu3, p = 0.003). The complete remission at the HSCT was observed in 79 % in Bu1, 49% in Bu2, 61% in Bu3 p=0,02. Probabilities of OS, RFS, TRM were estimated by using the Kaplan-Meier method. Incidence of toxicity, acute GVHD and primary graft failure - by using Mann - Whitney U-test. Results. Transplant engraftment was achieved in 95 (86%) of patients. Graft failure occurs in the 5 patients of Bu1 group (15%), in the 6 pts of Bu2 (17%) and in the 4 pts of Bu3 (10%), p=0,7. Median follow-up was 2 years for Bu1 and Bu3, 1 year for Bu2. OS was similar (Bu1=59% vs Bu2=60% vs Bu3=51%), p=0,7. OS of pts with CR before HSCT was 70% in Bu1, 82% in Bu2, 60% in Bu3, p=0,3 and 14%, 39%, 38% for pts with progression disease (PD), respectively, p=0,5. RFS was 74% in Bu1, 82% in Bu2, 64% in Bu3 at CR, p=0,4; 43%, 39% and 38% in pts with progression, respectively, p=0,9. Median of RFS were also similar for the pts in PD, (4 months in Bu1, 5 months in Bu2 and Bu3), p=0,9 and not achieved for pts at CR. Drug related toxicity grade 3-4 experienced in 35% pts in Bu1, 29% in Bu2, in 54% in Bu3, p=0,04. Mucositis and toxic hepatitis were the most common adverse events. Sinusoidal obstruction syndrome (SOS) experienced in 8 pts from different group: 4 from Bu2 (11%), 3 from Bu3 (7%) and only 1pts from Bu1 (3%) with previously treated of gemtuzumab ozogamicin, p=0,4. The most pts with SOS (3/5) had PD at the HSCT. Cumulative incidence of acute GVHD grade 2 (15% vs 14% vs 10%, p=0,8) were not different. Acute GVHD grade 3-4 was observed a bit more often in Bu3 (34%), than in Bu1 (18%) and Bu2 (17%), p=0,09. TRM up to +100 days was also higher in Bu3 (15%), than in Bu2 (6%) and Bu1 (0%), p=0,05. Conclusions. The transplant results of children with similar disease status of AML, received conditioning with various dose of busulfan, were not associated with significant differences in overall outcomes. The higher dose busulfan may increase incidence of toxicity grade 3-4 (p=0,04) and acute GVHD grade 3-4 (p=0,09) with increasing of early TRM (p=0,05). Disclosures Moiseev: Celgene: Consultancy, Other: Travel grants; Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; Pfizer: Other: Travel grants; MSD: Other: Travel grants; BMS: Other: Travel grants; Takeda: Other: Travel grants.

Description: Introduction: The programmed-death 1 blockade with nivolumab demonstrated high efficiency in patients with relapsed and refractory Hodgkin lymphoma (rrHL) with acceptable toxicity profile. However, most of the patients treated with immune checkpoint inhibitor (CPIs) will eventually progress on this therapy. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with rrHL. Therefore, allo-HSCT is a consideration for selected patients with HL after treatment with CPIs. There are concerns that CPIs before allo- HSCT may increase the incidence of graft-versus-host disease, immune-related adverse events, and nonrelapse mortality (NRM). At present, there is no consensus regarding the optimal transplant strategy for patients previously treated with immune checkpoint blockade. The aim of this study was to evaluate outcomes in patients with rrHL who received CPIs as a bridge to allo-HSCT. Patients and methods: We retrospectively evaluated the results of allo-HSCT in 22 patients who had been transplanted after prior PD-1 blockade between 2017 and 2019 at the R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology at the First St. Petersburg State Pavlov Medical University (CIC 725). All patients received reduced-intensity conditioning regimen (fludarabine 30 mg/m2, bendamustine 130 mg /m2 per day for 3 days (FluBe)) and post-transplant cyclophosphamide-based GvHD prophylaxis (PTCy). Patients received immune checkpoint inhibitors before allo-HSCT as a single-agent nivolumab or in combination with brentuximab vedotin or chemotherapy. The best response to PD-1 therapy was a complete response (CR) in 9 patients, partial response in 5 patients, 5 patients received transplant during the disease progression and 3 patients were transplanted in indetermined response according to the LYRIC. Patients received a median of 20 (range, 6-32) cycles of a PD-1 inhibitor. The median time from the last dose of anti-PD-1 therapy to HSCT was 83 days (range, 50-350). Results: At the time of analysis, median follow-up was 14 months (range, 1-26 months). Ninety one percent of patients engrafted. One patient had primary graft failure and one died on the day of the haploidentical graft transfusion due to cytokine release syndrome. The 1-year OS and EFS were 91% and 78% respectively, whereas the 1-year cumulative incidences of relapse and NRM were 9% and 9% respectively.Two patients with relapse after allo-HSCT were treated with donor lymphocyte infusion (DLI) in combination with chemotherapy. Both patients remain alive. 4/20 of the engrafted patients developed grade 2 GvHD and all responded to steroids. 4/20 patients developed severe grade 3-4 GvHD and only 1 patient responded to steroids. The cumulative incidence of chronic GVHD (cGVHD) was 35%, including 3 patients with severe, steroid-refractory cGVHD. There were no other immune-related adverse events. No cases sinusoidal obstruction syndrome was observed Conclusions: Our study demonstrates that HSCT after PD-1 blockade is feasible and not associated with higher mortality. We suggest that prior PD-1 blockade should not be considered a contraindication to HSCT in patients with relapsed and refractory Hodgkin lymphoma. severe The rate of severe acute and chronic GvHD was relatively higher than previously reported for PTCy-based prophylaxis, but was manageable in the majority of cases. The time between anti-PD-1 therapy and allo-HSCT and PTCy is likely to be important in the successful outcome of the transplant. Disclosures Moiseev: Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; MSD: Other: Travel grants; Celgene: Consultancy, Other: Travel grants; Takeda: Other: Travel grants; Pfizer: Other: Travel grants; BMS: Other: Travel grants.

Description: Background: Allo-HSCT with myeloablative conditioning (MAC) has traditionally been performed in patients with ALL and has been associated with significant transplant-related morbidity and mortality. Reduced-intensity conditioning (RIC) is used in patients not eligible for conventional conditioning therapy due to poor performance status and severe toxic complications after previous chemotherapy. RIC is a well-established treatment strategy in adult patients with comorbidities or in elderly patients. In contrast to the adults, the RIC pediatric experience is still sparse. The aim: to compare efficacy of reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) for allo-HSCT in children suffering from very high risk (VHR) ALL. Patients and methods: This was a retrospective analysis performed in 233 patients (pts) with ALL (age - from 4 month till 18 y.o. (mediana 11 y.o.)), who received allo-HSCT at R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation between 12/2000 and 12/2017. MAC (busulfan or treosulphan containing) was used in 159 pts: 1st CR - 26 pts, 2nd CR -57 pts, 3rd or 4th CR 23 - pts, relapse -53 pts. Allo-HSCT with RIC was performed in 74 pts: 1st CR - 14 pts, 2nd CR -29 pts, 3rd or 4th CR - 12 pts, relapse -20 pts. RIC consisted of fludarabine (30 mg/m2/d x 5 days) + melfalan (70 mg/m2/d x 2 days) or fludarabine (30 mg/m2/d x 5 days) + busulfan (4 mg/kg/d x 2 days). The disease status was not different between groups (p=0.674) Indication for RIC allo-HSCT was poor performance status (Lanskoy/Karnovsky=0,5x109/l was D+18 (range D+8-48). Transplant engraftment was observed in 64 pts (86%) after RIC and 150 pts (93%) after MAC (p=0,224). OS pts after RIC allo-HSCT performed in 1 CR 70% and after MAC - 85% (p=0,043), in 2 CR 56% after RIC and 49% after MAC (p=0,436), in 3 or 4 CR 34% after RIC and 25% after MAC (p=0,394). OS in patients with active disease was 16% in RIC-group and 18% in MAC-group (p=0,432). The transplant-related mortality rate was 18% after RIC and 20% after MAC (p=0,40). Risk of relapse was 37% after RIC and 42% after MAC (p=0,39). Acute GVHD II-IVgr developed in 32% pts after RIC and 33% after MAC (p=0,883), early infections were diagnosed in 63% in RIC-group, and 59% in MAC-group (p=0,356). Early toxic complications were observed (CTC): mucositis III-IV gr in 13% pts after RIC and in 54% pts after MAC (p=0,001), nephrotoxicity in 7% pts and in 21% pts (p=0,042), hepatitis gr II-III in 24% pts and in 57% pts, respectively (p=0,034), neurological complications in 22% pts and 42% pts, resp. (p=0,046). Conclusion: RIC allo-HSCT of VHR ALL in 2,3 or 4 CR pts ≤ 18 y.o. is effective and comparable with MAC allo-HSCT. Early toxic complications after RIC were less frequent. Possibly, the use of RIC can maintain efficacy while minimizing regimen-related toxicity in children who have undergone previous intensive treatment. Disclosures Moiseev: Pfizer: Other: Travel grants; BMS: Other: Travel grants; MSD: Other: Travel grants; Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; Celgene: Consultancy, Other: Travel grants; Takeda: Other: Travel grants.

Description: 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

Description: Background Currently, the recommended dose of nivolumab for patients with relapsed or refractory classical Hodgkin lymphoma (r/r сHL) is 3 mg/kg. Nevertheless, published clinical cases indicate the possible efficacy of lower doses of nivolumab. Moreover, experimental studies provided the rationale for possible reduction of nivolumab dose in patients with solid tumors (Agrawal et al. 2016). The presented data creates prerequisites for studying the lower nivolumab doses efficacy and safety in the r/r cHL therapy. Patients and Methods This study included 42 patients (14 male/28 female) with r/r cHL who were treated with nivolumab 40 mg every 2 weeks. The median age of patients was 36 (22-53) years. The median number of prior therapy lines was 4 (2-7). Prior treatment contained high dose chemotherapy with ASCT in 9 pts (21%), brentuximab vedotin in 14 pts (33%) and allo-HSCT in 1 pt (2%). Four pts (9,5%) had the partial response (PR) and the remaining 38 pts (90,5%) had the disease progression (PD) at the moment of nivolumab initiation. B-symptoms were present in 23 pts (55%), ECOG status was grade 0-I in 25 pts (59,5%), grade II in 12 pts (29%), grade III in 4 pts (9,5%) and grade IV in 1 pt (2%). The primary endpoint was the overall response rate (ORR) determined by positron-emission tomography/computed tomography (PET/CT) using LYRIC criteria every 3 months. Key secondary endpoints included progression-free survival (PFS) and overall survival (OS). Adverse events (AE) were evaluated according to CTCAE 4.03. The patient group characteristics were evaluated using descriptive statistics methods, the survival analysis was performed using Kaplan-Meyer method (SPSS Statistics v.17). Results The median number of nivolumab cycles was 24 (2-38). The response was evaluated in 41 out of 42 pts. The ORR was 66%. The best response included complete response (CR) in 39%, PR in 27%, stable disease in 5%, PD in 2%, indeterminate response (IR) in 27% of pts. With a median follow-up of 27,5 mo (11,3-34,5) 41 pts (97,6%) were alive, the median OS was not reached. The 2-year PFS was 44,5% (95% CI, 28,2-59,6) The nivolumab therapy was discontinued in 39 pts (93%) due to scheduled discontinuation in 14 pts (33%), PD in 13 pts (31%), grade 3-4 AE in 2 pts (5%), change of therapy because of insufficient response in 6 pts (14%) and other reasons in 4 pts (10%). The progression of disease during nivolumab therapy was present in 14 (33%) pts and after nivolumab discontinuation in 6 (14%) pts. After disease progression 30 pts (71%) were retreated with nivolumab monotherapy or in combination with chemotherapy. The median time to additional therapy was 14,5 mo (4,2 -32,9). The adverse events of any severity were observed in 30 pts (71%). Grade 3 or higher AE were present in 4 pts (9,5%), including grade 3 arthralgia, grade 3 anemia, grade 4 pneumonia and pneumonitis, grade 4 increased level of alanine aminotransferase and grade 5 MDS in 1 pt. A significant reduction of PD1+CD3+ cell population of peripheral blood lymphocytes was observed after first nivolumab cycle (median 0.7% (0-1.7) versus 33% (15.7-80.1) before therapy initiation, p = 0.02, Wilcoxon signed-rank test). Conclusion Our study demonstrated the efficacy and safety of nivolumab 40 mg therapy. The presented results are comparable to previously published data of nivolumab 3 mg/kg therapy in patients with r/r cHL. Thus, this creates a basis for further direct comparative study of nivolumab efficacy in different doses Disclosures No relevant conflicts of interest to declare.

Description: Background Immune checkpoint (IC) inhibitors (ICI) is a promising group of agents with potential effect in myelodysplastic syndrome (MDS). However, there is not enough data on the pattern of IC expression in MDS bone marrow, though this can guide future therapies with ICI. Methods We prospectively included 57 patients with high risk MDS during 2019-2020 years after signing informed consent for participation in research. We used 7 eight-colored panels in each patient to define IC expression on T- and NK-cells (CD3, CD8, CD4, CD56, CD16), myeloid precursors (CD117, CD34), T-regulators (CD25, CD4), myeloid-derived suppressor cells (CD15, CD11b, CD14, HLA-DR, CD33). In each population we assessed expression of CD279, CD152, CD223, TIM3, CD273, CD274, CD275, CD80. Results In lymphoid populations we observed an extremely high percentage of PD-1 positive lymphocytes (10.5 ± 8.0% of all nucleated cells), including PD-1 positive CD4 lymphocytes (6.3 ± 3.7%) and CD8 lymphocytes (4.7 ± 3.5%). Interestingly, on average 63 ± 34% of all lymphocytes were PD-1 positive (Figure 1A), which indicates an extreme degree of T-cell exhaustion and significant exploitation of the PD-1 system by a malignant tumor. Among the PD-1 ligands PD-1L predominated, however it was present only on a small percentage of myeloid precursors (2.2 ± 0.39% of nucleated cells), but most of the PD-1L ligand expression was observed on granulocytes in the process of their differentiation from myeloid precursors (5.8 ± 4.1% of nucleated cells), and in some patients the proportion of such granulocytes reached more than 20%. Moreover, on the cells of the monocytic series, PD-1L is practically not expressed, but CD80 is expressed, a ligand for CTLA4 (1.6 ± 0.7% of nucleated cells). Interestingly, despite the presence of expression of CD80 on monocytic and dendritic cells, the receptor for this ligand on T-lymphocytes was practically absent. The proportion of such cells was only 0.02 ± 0.01%, i.e. the expression of CD80 facilitates the activation of lymphocytes through interaction with CD28 rather than the suppression of the immune response through CD152. Thus, it can be suggested that CTLA4 does not have a clinically significant role in MDS. At the same time, a certain number of TIM3 positive lymphocytes were observed, the proportion of which was 0.42 ± 0.16%, and the percentage of lymphocytes carrying this receptor was 3.6 ± 1.2% (Figure 1A). However, significantly greater TIM3 expression was detected on NK cells. The proportion of such cells was 1.3 ± 0.6% of all nucleated cells, while 30% of all NK cells carried the TIM3 receptor (Figure 1A). Only 0.1% of cells from early myeloid progenitors that expressed TIM3 receptor were detected during flow cytometry, while the proportion of TIM3 positive myeloid cells increased during maturation just in the same way as the PD-1L. Expression of Gal9 was negligible, as it is a protein secreted into the intercellular space. Only a small percentage is associated with cell membranes. The analysis of the correlation matrix showed synchronous changes in the number of most bone marrow T-cell populations. A negative correlation of the level of myeloid tumor precursors actively expressing IC ligands and activated T cells, expressing CD223, NK cells, NKT was observed. The total number of myeloid tumor precursors positively correlated with the number of PD-1 positive lymphocytes (Figure 1B). Conclusion It was found that IC system plays a role in high-risk MDS. Moreover, the expression of ligands is mainly realized during maturation of blast cells into granulocytes, which are the main population expressing these inhibitory molecules. The leading role in the suppression of the T-cell response in MDS is played by the PD-1-PD-1L system, the CTLA4 system plays a minor role in our study cohort. The second most important system is GAL9-TIM3, effecting predominantly NK cells, while T cell are less affected. Thus, the data obtained justify the trials of dual blockade with anti-PD-1 and anti-TIM3 agents in high-risk MDS. Figure 1 Disclosures No relevant conflicts of interest to declare.