ALBERT

Description: AN and MM are co-senior authors. Background. Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are two widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (allo-SCT). Patients and Methods. In the current survey, we compared transplantation outcomes in a cohort of 394 acute myeloid leukemia (AML) patients given grafts from HLA-identical siblings after FB (n=218; with a total busulfan dose ranging between 7.1 and 8.9 mg/kg p.o., or between 6.0 and 6.9 mg/kg i.v.) or FM (n=176; with a total melphalan dose ranging between 130 and 150 mg/m2). Patients given manipulated grafts and those given T cell depleting agents (ATG or alemtuzumab) were not included. At time of transplantation, 266 patients (68%) were in first complete remission (CR1), 69 (18%) in later CR, while 59 patients (15%) had advanced diseases. Three-hundreds and fifty-two patients (89%) received peripheral blood stem cells while the remaining 42 patients received bone marrows as stem cell source. Results. Three FB patients but no FM patients failed to engraft. Median time for reaching 500 neutrophils was 17 (1-50) days in FB patients versus 14 (9-43) days in FM patients (P

Description: Background: Allogeneic hematopoietic cell transplantation (alloHCT) is a complex therapy which can induce a multi-factorial cascade of complications, and potentially lead to patient death. The triggering event(s), sequence and severity of such complications can significantly differ between patients, but in many cases, a so-called "multi-organ failure" (MOF) is usually reported as the leading cause of death. However, a patient's clinical course can be very heterogeneous across and within cause-specific mortalities. Moreover, comorbidities present prior to alloHCT carry their own risks and represent additional confounding factors. Therefore, identification of the exact initial trigger or event leading to MOF in alloHCT patients is a critical step towards early intervention and improvement of patients' outcome. The goal of the current study was to establish and identify the exact cause of death in alloHCT patients where MOF was considered to be the main cause of death. Of note, we specifically focused on VOD/SOS because this life-threatening complication has a mortality exceeding 80% in severe cases, ending usually in MOF, and because VOD/SOS has subtle and dynamic evolution features which are not easy to capture, but could be potentially controlled by appropriate therapy (eg. defibrotide). Patients and Methods: For the purpose of this analysis, we randomly identified 241 adult patients (42% female; median age: 50 years; range 19-73) with acute leukemia (72% AML, 25% ALL, 3% other) allografted between 2010 and 2018 from a matched sibling (29%), unrelated (61%) or haploidentical donor (10%). All patients were reported to the EBMT registry to have died from MOF. Karnofsky score at time of alloHCT was 〉90 in 87% of patients. Seventy-three percent of patients underwent transplant in complete remission, and conditioning was myeloablative in 70%. Sixty patients (25%) received VOD/SOS prophylaxis treatment, mainly consisting of ursodiol and/or heparin. Patients' files were reviewed in detail in order to capture all early signs and symptoms which occurred prior to MOF, based on the classical Baltimore criteria, modified Seattle criteria, and/or the newly published EBMT criteria. These criteria included bilirubin levels, the presence of hepatomegaly or painful hepatomegaly, ascites, percentage weight gain, hemodynamic instability, and ultrasound/histologically proven VOD/SOS. Results: Using one or more of the above criteria defining VOD/SOS, we identified a total of 67 (28%) patients for whom VOD/SOS could be considered as the trigger for MOF and the leading cause of death. Interestingly, among these 67 patients, only 22 (33%) were originally reported by the centers as having developed VOD/SOS leading to MOF post-transplant. When comparing the group of 67 patients dying of VOD/SOS-related MOF and the remaining 174 patients dying of MOF not related to VOD/SOS (please see attached table), a multivariate regression analysis identified a significant increase in VOD/SOS incidence (odds ratio 3.9; 95%CI, 2.42-6.33; p

Description: Myeloproliferative disorders (MPD) are a heterogeneous group of diseases that involve chronic myeloid leukemia (CML), polycythemia vera (PV), essential trombocythemia (ET), chronic idiopatic myelofibrosis (IMF), hypereosinophilic syndrome and chronic neutrophilic leukemia. Recently, it has been found that in Ph-negative MPD, acquired somatic mutation in JAK2 gene can be identified, causing substitution of valine for phenylalanine at aminoacid position 617 (V617F). Experimental evidence indicates that JAK2 V617F might cause erythropoietin-independence of erythroid colonies and receptor hypersensitivity, thus be implicated in the pathogenesis of PV. The incidence of V617 in PV is high, reaching 96% of cases; in ET or IMF, the mutation is less frequent. Nevertheless, the percentage of JAK2 V617F-positive patients differs greatly among studies, depending on the detection technique used. Sequencing analysis, as one of the options, can underrate the number of positive cases, as its sensitivity in authentic samples with varying proportion of mutant granulocytes is unsatisfactory. The nucleotide context of the V617F site is complicated (direct repeat TGTG/TT), and thus prone to sequencing artifacts. For specific and sensitive detection of V617F mutation in JAK2 gene, we have developed a novel allelic discrimination assay, based on the usage of Real-Time PCR technology and LNA-modified fluorescently labeled probes (Locked Nucleic Acids). This technology is distinguished by 100% discrimination efficiency, and sensitivity detection rate reaching 10% of mutant granulocytes in an authentic sample. LNA-modified probes are extremely powerful tool for precise genotyping, since they are short (12-mers), and due to the interspersed LNA nucleotides, melting temperature (Tm) of the probe/target hybrid is high. Hence, the LNA-based genotyping technology combines the desired features of high sensitivity and absolute specificity. Herein, we present an analysis of JAK2 V617F detection in our group of 157 consecutive patients with the diagnosis of MPD or suspected MPD. Using our novel LNA-based Real-Time PCR genotyping technique, we were able to identify varying proportions of the mutant JAK2 allele in 87 cases (55.4%); in the remaining 70 patients the mutation was not detected. The LNA-based Real-Time PCR technique is extremely precise and efficient in identifying even subtle proportion of JAK2 V617F mutant granulocytes, which in cases of diagnostic uncertainties on the origin of the polycythemia might be of great importance.

Description: Background: NLPHL is a relatively uncommon subtype of Hodgkin lymphoma (HL) accounting for about 5-6% of all HL cases. It has unique clinico-pathological, morphologic and immunohistochemical features with CD20-positive "lymphocyte predominant cells". Although long-term survival is better than in classical HL, frequent relapses are common and progression/transformation to aggressive non-Hodgkin lymphoma (NHL) may occur. Whilst HDC auto-SCT is considered as standard of care for relapsed/refractory classical HL, data on HDC auto-SCT in relapsed/refractory NLPHL is sparse. Here, we report a registry study of HDC auto-SCT for NLPHL using the EBMT database, representing the largest sample analyzed to date. Design: Eligible were patients with NLPHL18 years or older who underwent a first auto-SCT between 2003 and 2013, and were registered with the EBMT. Patients with NLPHL transformed to DLBCL were not eligible. The primary objective was 5-year progression-free survival (PFS). Baseline patient, disease and transplant data were collected from EBMT MED-A standard forms. Centers with potentially eligible patients were contacted to provide additional treatment and follow-up details with a copy of written diagnostic report for central review. Statistical analysis was descriptive and employed log rank comparisons for univariate assessment of the impact of baseline characteristics on survival endpoints. Results: We identified 92 patients who met the inclusion criteria with full data including a written diagnostic pathology report available. Of these, 36 patients were excluded after histopathology report review (17 classical HL, 2 NHL, 17 no sufficient information). The final sample comprised 56 patients. There was a predominance of male patients with a male:female ratio of 88%:12%. Median age was 36 (interquartile range (IQR) 29-50) years. Most patients (65%) had advanced stage (III-IV) at diagnosis and one third had B-symptoms. Prior to HDC auto-SCT, 71% patients had 2, 20% had 3, and the remainder had more than 3 lines of treatment (median: 2 lines). Rituximab was used in 62% of patients. The median time from diagnosis to HDC auto-SCT was 21 (IQR 14-51) months. Disease status prior to HDC auto-SCT was complete remission (CR) in 54% and partial remission (PR) in 43%. Most commonly used HDC was BEAM (84% patients), with additional rituximab in 13%. With a median follow-up of survivors of 5 (IQR 3.6-6.6) years, 5-year PFS and overall survival were 67% (95%CI 55-82) and 86% (95%CI 77%-96%), respectively. The 5-year incidence of relapse was 32% (95%CI 20-46). There were no transplant-related deaths. Univariate comparisons considering age, time from diagnosis to transplant, number of pre-treatment lines and rituximab use during induction, salvage and/or HDT failed to identify significant predictors of PFS or OS endpoints. Conclusions: This study, the largest reported thus far on HDC auto-SCT in NLPHL, shows that two thirds of patients remain free of disease 5 years after HDC auto-SCT. In contrast with the usual characteristics of patients with NLPHL, those included in this series had high-risk disease with B-symptoms and advanced stage at diagnosis, and half the patients had HDC auto-SCT less than 2 years after diagnosis. This study demonstrates that patients with NLPHL and adverse features can benefit from HDC auto SCT at relapse. Figure. Figure. Disclosures Montoto: Roche: Honoraria; Gilead: Research Funding. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Moraleda:Pfizer: Research Funding. Bloor:Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Meissner:Amgen: Other: Travel Support; Takeda: Other: Travel Support; Celgene: Other: Travel Support; Teva: Other: Travel Support. Dreger:Novartis: Speakers Bureau; Gilead: Consultancy; Gilead: Speakers Bureau; Novartis: Consultancy; Janssen: Consultancy; Roche: Consultancy.

Description: Key Points In AML with normal cytogenetics, age, response to induction, and FLT3-ITD allow for an estimate of outcome after allogeneic HSCT in CR1. Neither variation of classical transplant techniques nor development of chronic GVHD outweighs the negative impact of FLT3-ITD.

Description: Aims: Treatment of multiple myeloma (MM) in relapsed and refractory setting (RRMM) has been a challenge. The best outcomes have been observed in triplet combination of novel drugs. However, most combinations require weekly parenteral administration thus degrading patients´adherence to therapy, especially when treatment is scheduled "until progression". The introduction of fully oral triplet combination ixazomib, lenalidomide and dexamethasone (IRD) showed an outstanding efficacy in the Tourmaline-MM1 trial. Our aim is to determine the efficacy and safety of IRD regimen outside clinical trials. Patients and methods: A cohort of 127 RRMM patients from the Czech and Slovak Republic were treated with IRD regimen within a Named Patient Program between 2016 and 2018. The M/F ratio was 1.2:1 with median age 66 years (41-84). The representation of M-protein and light chain types as well as ISS stage was standard. The data for cytogenetics were recorded only at the time of diagnosis in 71% of patients with 15 patients having high-risk features - t(4;14), t(14;16) and del17, and 41 patients having standard risk features. In 34 patients we were not able to determine the risk status as at least one abnormality was missing and none was positive. The presence of extramedullary plasmocytoma was recorded in 15% of patients. Most patients received IRD for their 1st relapse (58.5%), followed by 2nd (23.7%) and 3rd relapse (7.6%) with significant portion of patients being treated in ≥4th relapse (10.1%). The pretreatment with individual drugs was as follows: bortezomib (BTZ) 94.5%, thalidomide (THAL) 40.9%, lenalidomide (LEN) 18.9% and carfilzomib 5.5%. 62.2% of patients underwent previous autologous stem cell transplant. Altogether 25.2% of patients were refractory to at least 1 drug with 18.9% being BTZ refractory and 7.9% LEN refractory. Data were analyzed from the Czech Registry of Monoclonal Gammopathies. Data were described by absolute and relative frequencies of categorical variables and mean (standard deviation), median (minimum-maximum) of quantitative variables. Survival measures were plotted using Kaplan-Meier methodology at 95% confidence interval, log-rank test was used to estimate the statistical significance at P

Description: Background : Outcomes reported in real-world practice versus controlled clinical trials show markedly shorter treatment durations, progression free survival (PFS) and overall survival (OS). Understanding effectiveness of therapeutic regimens in routine practice is critical for treating physicians as well as for regulatory and reimbursement authorities. We have performed a real-world comparison of two regimens, ixazomib, lenalidomide and dexamethasone (IRD) triplet and lenalidomide and dexamethasone (Rd) doublet in patients with relapsed and/or refractory multiple myeloma (RRMM) treated in seven Czech and one Slovak hematology-oncology centers. Patients and methods: Between 3/2015 and 5/2017, 344 patients with RRMM were treated with either IRD (N=127) or RD (N=217). Patients selected for both cohorts had the same inclusion and exclusion criteria. Patient baseline characteristics were well balanced. The data were collected through the Czech Registry of Monoclonal Gammopathies (RMG), which is an international database gathering data from patients with monoclonal gammopathies within Central Europe. Results: The median follow-up in the IRD vs RD arm was 20.8 vs 15.5 months, respectively. Median PFS in pts with 1-3 prior lines for the IRD cohort was 23.1 months (95% CI 11.8-34.5 months) and 11.6 months (95% CI 8.4-11.8 months) for the RD cohort favoring the all-oral triplet (p=0.001). The median PFS for all patients including 4+ line of therapy was 17.5 months (95% CI 10.3-24.7) in the IRD cohort versus 11.5 months (95% CI 8.6-14.3) in the RD group (p=0.005). Median OS for pts with 1-3 prior lines for IRD cohort was not reached, and was 27.1 months (95% CI 23.1-31.1 months) in the RD cohort (p=0.002). Median OS for all patients, including 4+ lines of treatment was 36.6 months in the IRD vs 26.0 months in the RD cohort (p=0.008). The PFS benefit of IRD over RD was observed in most of the assessed subgroups; in younger pts ≤65 years with hazard ratio (HR) 0.58, in pts 66-75 years HR 0.64. There was a trend towards better PFS in patients with lower ISS stage; ISS1 HR 0.53, ISS2 HR 0.58 and ISS3 the HR was 0.87. Patients in the 1st relapse (HR 0.53) benefited most from the IRD, followed by the 2nd relapse (HR 0.58), 3rd relapse (HR 0.90) and pts relapsing after 4+ therapies (HR 0.88). The PFS benefit of IRD regimen was observed in pts regardless of previous stem cell transplantation; transplant-eligible patients HR 0.51 and transplant-ineligible HR 0.71. Patients who did not benefit from the triplet regimen were those over 75 years of age and pts with the presence of extramedullary disease. The IRD treatment was well tolerated. The safety profile was concordant with previously reported data. Conclusions: This RMG comparative cohort analysis shows PFS benefit of all-oral IRD regimen over RD in the real world setting, and confirms growing evidence that long term outcomes with IRD triplet are comparable with phase 3 TOURMALINE-MM1 trial. Our analysis also shows an overall survival benefit of IRD over RD treatment. Patients older than 75 years, with 4+ lines of therapy and presence of extramedullary disease did not profit from addition of ixazomib to RD doublet.Additional data with larger patient populations confirming RWE effectiveness are warranted. With support of AZV 17-29343A, NV18-03-00500, FNOl 00098892, IGA-LF-2019-001, PROGRES Q40/08, MH CZ-DRO (UHHK, 00179906) Disclosures Minarik: Celgene: Consultancy, Honoraria, Research Funding; Amgen, BMS, Janssen-Cilag, Takeda: Consultancy, Honoraria. Straub:Amgen, Takeda, Celgene: Consultancy. Spicka:Celgene: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Sanofi: Consultancy. Skacel:Millennium Pharmaceuticals, Inc., subsidiary of Takeda Pharmaceutical Company Limited: Employment. Maisnar:Janssen, Amgen, Celgene, Takeda, BMS: Consultancy, Honoraria.

Description: Introduction: The prognosis of patients diagnosed with blast crisis (BC) chronic myeloid leukemia (CML) is dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option. In the current tyrosine kinase inhibitor (TKI) era, however, data on transplant outcomes in patients with BC CML, particularly those with active BC at transplant, are scarce. We hereby report on a multicentre, EBMT-registry based retrospective study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. Patients and methods: Patients with BC CML at transplant (i.e. prior to the start of the conditioning) who underwent alloSCT after the year 2004 within the EBMT database were identified. Next, transplant centers were asked to report the exact disease status at transplant (including blood count, blast count in peripheral blood and bone marrow, achievement and type of remission with corresponding assessment dates, and the reason to proceed with alloSCT in BC CML). A total of 170 patients allografted for BC CML between 2004 and 2016 had complete data for analysis. Overall survival (OS) and leukemia-free survival (LFS) were calculated from date of alloSCT to the appropriate endpoint. For multivariable analysis of predictors of OS and LFS, Cox proportional hazard regression models were performed. Confounding prognostic factors (full models) were: age, disease status prior to alloSCT, Karnofsky performance status (KPS) prior to transplant, interval from diagnosis to transplant, year of transplant, stem cell source, conditioning intensity, donor type, and donor/recipient sex match. All patients provided informed consent for data collection and analysis. Results: Median age at alloSCT was 45 years (range [r], 18-75). Median time from diagnosis to alloSCT was 13.9 months (r, 1.6-367.4). Median follow-up time was 54.7 months (r, 0.1-135.2). Stem cell source was peripheral blood, bone marrow and cord blood in 145 (85%), 18 (11%) and 7 (4%) patients, respectively. Donor types were: unrelated (UD), matched related, and mismatched related in 91 (54%), 64 (38%), and 15 (9%) patients, respectively. Conditioning was myeloablative in 108 (64%) of patients. KPS at alloSCT was ≤80% in 31% of patients. Information on BCR-ABL mutations was available for 41 patients; T315I was present in 28 patients. After thorough analysis of disease parameters, a total of 95 patients had any kind of remission of BC CML (including secondary chronic phase) prior to transplant (termed BC in remission); 75 patients had active BC CML prior to transplant (termed BC active). Main reason for proceeding with alloSCT despite active disease was resistance/refractoriness towards TKI in combination with polychemotherapy. Extramedullary disease was documented in 4 patients. In uni- and multivariable analyses of the entire cohort, besides low KPS, only disease status prior to transplant was significantly associated with shorter OS and LFS (for BC active: HR 2.00, 95%CI 1.35-2.96, p=0.001 and HR 1.80 95%CI 1.27-2.57, p=0.001, respectively). Accordingly, for patients allografted for active BC estimated 3-year OS and LFS was rather short (23.8% 95%CI 13.6-34.0 and 11.6% 95%CI 3.0-20.2, respectively) and significantly lower as compared to patients allografted for BC in remission (3-year OS and LFS: 51.1% 95%CI 40.5-61.7 and 33.8% 95% CI 23.6-44.0, respectively) (Figure 1A and B). Consequently, prognostic factors for survival were analyzed separately according to disease status at alloSCT (slim models, Table 1). For patients with BC in remission at transplant advanced age, lower KPS, shorter interval from diagnosis to transplant, myeloablative conditioning, and UD transplant were risk factors for inferior survival, whereas in patients allografted for active BC, only UD transplant was associated with prolonged LFS and with a trend towards improved OS (Table 1). Conclusion: Survival of BC CML patients after alloSCT in the TKI era remains poor unless disease remission could be achieved. In patients who achieve remission prior to alloSCT, conventional prognostic indicators remain the determinants of transplant outcomes. In patients with active BC CML, UD transplantation appears to be associated with a survival advantage in our study. Disclosures Finke: Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mayer:Eisai: Research Funding; Roche: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Description: Relapsed acute myeloid leukemia (AML) is a significant post-transplant complication lacking standard treatment and associated with a poor prognosis. Cellular therapy, which is already widely used as a treatment for several hematological malignancies, could be a potential treatment alternative. Natural killer (NK) cells play an important role in relapse control but can be inhibited by the leukemia cells highly positive for HLA class I. In order to restore NK cell activity after their ex vivo activation, NK cells can be combined with conditioning target cells. In this study, we tested NK cell activity against KG1a (AML cell line) with and without two types of pretreatment—Ara-C treatment that induced NKG2D ligands (increased activating signal) and/or blocking of HLA–KIR (killer-immunoglobulin-like receptors) interaction (decreased inhibitory signal). Both treatments improved NK cell killing activity. Compared with target cell killing of NK cells alone (38%), co-culture with Ara-C treated KG1a target cells increased the killing to 80%. Anti-HLA blocking antibody treatment increased the proportion of dead KG1a cells to 53%. Interestingly, the use of the combination treatment improved the killing potential to led to the death of 85% of KG1a cells. The combination of Ara-C and ex vivo activation of NK cells has the potential to be a feasible approach to treat relapsed AML after hematopoietic stem cell transplantation.

Description: Key Points The expression level of patient HLA-C allotypes affects GVHD and mortality after HCT from HLA-C-mismatched unrelated donors. Transplant outcome can be improved by avoiding high-risk HLA-C-mismatched donors when no matched stem cell source is available.