Abstract: Abstract 4097 A small subset of patients with hypereosinophilic syndrome (HES) presents an interstitial deletion in chromosome 4q12, which leads to the expression of an imatinib -responsive fusion gene- called FIP1L1-PDGFRA (F/P). These patients have chronic eosinophilic leukemia (CEL). Here, we treated twenty five F/P-positive CEL patients (22 male, 2 female; median age of 50 years) with imatinib using initial daily doses ranging from 100 – 400 mg. At diagnosis a median peripheral blood eosinophilia and eosinophil marrow infiltration were 12×109/L (range 2.5–40.8) and 39% (range 7–80), respectively. Splenomagaly was the most frequent clinical manifestation in this patient subgroup. All imatinib-treated patients achieved clinical and molecular response. A complete haematological remission (CHR) was demonstrated after median of 13 days (range 3–90) whereas molecular response (MR) was confirmed after median of 9 months (range 3–24). In a remission maintenance phase, imatinib doses were de-escalated and they were following: 100mg once weekly (n=11), 100mg twice weekly (n=6), 100mg daily (n=5), 200mg once weekly (n=2) and 400mg once weekly (n=1). Plasma imatinib level was measured 24 hours after the last drug intake in 7 patients treated in once weekly schedule and it remained extremely low, ranging between 44–167 ng/ml. Molecular studies performed at the same time points confirmed molecular remission. With a median follow-up of 40 months all patients remained in CHR and FIP1L1-PDGFRA expression was undetectable in all treated patients. These data indicate that even very low imatinib doses are highly effective in remission maintenance of patients with F/P-positive CEL. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background Brentuximab vedotin (BV) is an effective salvage treatment in patients with relapsing/progressive Hodgkin lymphoma (HL). However, it is unclear how much BV improved the outcome of BV naïve patients who relapsed after autologous hematopoietic stem cell transplantation (autoHCT) in real life. To address this question, we compared the outcome of patients who received conventional salvage treatment before the BV era to those who were treated with BV in haematological centres allied within the Polish Research Study Group. The goals of the study were to compare: the response rates to the conventional salvage chemotherapy and to the BV-based treatment, the proportion of patients proceeding to subsequent allogeneic (allo) or second autologous HCT and finally the overall survival (OS), and progression-free survival (PFS) of relapsing patients after autoHCT treated with and without BV. Methods and study group The study group consisted of adult patients with classical HL relapsing after first autoHCT who were treated either with conventional salvage chemotherapy (between 2001 and 2013; Group 1, n=121) or BV based treatment (between 2012 and 2018; Group 2, n=44). The groups did not differ in terms of age or gender. The patients in Group 2 received more chemotherapy lines before post-transplant salvage treatment (median 3, range 1-6) compared to those in historical Group 1 (median 2, range 1-6) (p=0.013). No patient was treated with immune check points inhibitors. The response to salvage treatment in the majority of patients in historical Group 1 was assessed with conventional computer tomography (CT), while in all patients in Group 2 with CT combined with positron emission tomography. Results The rate of the objective response rate defined as the complete or partial response was higher in Group 2 (84% vs 60%, p 〈 0.001). Of a total of 121 patients in Group 1, 34 (28%) proceeded to the second autoHCT, and 27 (22%) to alloHCT, compared to 4 (9%) and 20 (45%) of 44 patients in Group 2, respectively (p=0.004). The median follow-up time of survivors is longer in the historical Group 1 compared to Group 2 (40 months vs 19 months, p 〈 0.001). However, at 2 years after the start of post-transplant salvage treatment, the estimated OS for patients in Group 1 was 55.2 % (95 % CI 45.8-64.3 %) compared to 81.9 % (95 % CI 66.5-91.2 %) for patients treated with BV (p=0.009) (figure). The respective estimated 2-year PFS was 41.2% (95 % CI 32.3-50.8 %) for Group 1 and 56.2% (95 % CI 38.5-72.4 %) for Group 2 (p=0.038). Importantly, the OS of patients who proceeded to alloHCT after BV-based salvage treatment was statistically significantly better compared to patients treated with alloHCT in the historical pre-BV group (2-year OS 81% vs 55%, p 〈 0.001). Conclusions In the era of brentuximab vedotin, significantly more patients with HL relapsing after autoHCT achieve objective response and proceed to allogeneic HCT. This most likely translates to the better PFS exceeding 24 months and most importantly to the significantly better OS of patients treated with BV compared to those treated with conventional salvage chemotherapy in the pre-BV era. Figure Disclosures Czyz: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dlugosz-Danecka:Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Macrogenomics: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jurczak:Gilead: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Roche: Research Funding; Servier: Research Funding; MorphoSys: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; Celtrion: Research Funding. Walewski:Gilead: Other: Travel Expenses; Bristol-Myers Squibb: Consultancy, 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, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wrobel:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zaucha:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: AML is the most common acute leukemia in adults. While most adults & lt; 60 years achieve complete remission (CR) with intensive induction chemotherapy, approximately one third have primary refractory disease and, overall, the majority of AML patients still relapse despite having attained initial remission (Dohner et al, Blood 2017). The combination of an anthracycline and cytarabine has been the mainstay of intensive AML induction for more than 50 years. Combined with cytarabine (AraC), high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of CR (70.6% vs. 57.3%, P & lt;0.001) and improved overall survival (OS) (median 23.7 vs. 15.7 months; P = 0.003), without increased serious adverse events compared with DA-45 (Fernandez et al, NEJM, 2009). In two PALG randomized trials, the combination of cladribine with DA (DAC regimen) also resulted in significantly increased CR after a single induction course, compared with the standard two-drug induction (DA-60) (Holowiecki et al, Leukemia, 2004 and JCO 2012). Both regimens have a recommendation from the National Cancer Comprehensive Network (NCCN) for routine use. For patients with primary refractory disease, the commonly used FLAG-IDA (fludarabine, cytarabine, idarubicin, GCSF) regimen results in a CR rate of 52% (Pastore et al, Ann Hem, 2003). Two previous PALG studies confirmed that another standard regimen, CLAG-M (a combination of cladribine, Ara-C, G-CSF and mitoxantrone) is also effective with tolerable toxicity in refractory/relapsed AML patients (Robak et al Leuk Lymph, 2000; Wrzesień-Kuś et al, Eur J Haematol 2003; Wrzesień-Kuś et al, Ann Hematol, 2005; Wierzbowska et al, Eur J Haematol ,2008; Jaglal et al, Leuk Res, 2014). PALG-AML1/2016 aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML. This trial is also the first international randomized trial in AML induction to prospectively evaluate the impact of measurable residual disease (MRD) on overall survival, using multi-modality testing (flow-cytometry, next-generation sequencing, and PCR) of serial samples. The study is conducted in accordance with the principles of the "Declaration of Helsinki". Study Design and Methods: PALG-AML1/2016 is a multicenter, randomized, Phase III study which will include 582 patients with newly-diagnosed AML treated at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City. This will allow a 10% difference in CR rate between the DAC and DA-90 induction regimens to be confirmed with a power of 80% and level of significance 0.05. Eligible patients must be 18 to 60 years of age with untreated AML, Eastern Cooperative Oncology Group performance status 0-2 and HCT-CI Index of comorbidities, ≤ 3. As midostaurin treatment has become approved and available the study was amended with an exclusion of FLT3-mutated patients. The trial schema is shown in Figure 1. The trial was initiated in July 2017 and 279 patients have been enrolled to date and accrual is ongoing. Preliminary safety and efficacy data were reviewed by the data safety monitoring committee after 194 patients and the recommendation was to proceed without changes. Serial samples for MRD are being collected from all patients at multiple time points and analysis is ongoing. ClinicalTrials.gov Identifier: NCT03257241 Figure 1 Disclosures Wierzbowska: Janssen: Honoraria; Celgen/BMS: Honoraria; Novartis: Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Research Funding. Pluta:Angelini: Research Funding; Celgene/BMS: Honoraria. Libura:Novartis: Honoraria. Wrobel:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Zaucha:Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Cellgene: Other: travel, accomodations, expenses; Novartis: Consultancy; BMS: Consultancy; Takeda: Consultancy, Honoraria, Other: travel, accomodations, expenses; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses. Robak:AstraZeneca: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Morphosys: Research Funding; UCB: Honoraria, Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UTX-TGR: Research Funding; BioGene: Honoraria, Research Funding; Acerta: Research Funding; Momenta: Consultancy; Pfizer: Research Funding; Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Medical University of Lodz: Current Employment; Takeda: Consultancy. Lee:BMS: Consultancy; Helsinn: Other: Member -DSMB; AstraZeneca: Consultancy; Jazz: Consultancy; Roche Molecular Systems: Consultancy. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria, Research Funding; Jazz pharmaceuticals: Honoraria, Research Funding. Guzman:Cellectis: Research Funding; SeqRx: Honoraria. Roboz:Agios: Consultancy; Amphivena: Consultancy; Astex: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy. OffLabel Disclosure: cladribine - in induction regimen in AML

Abstract: Abstract 2874 Introduction Cytogenetic abnormalities are concerned the major novel prognostic factors in patients with newly diagnosed multiple myeloma (MM). Chromosome 1 abnormalities, mainly 1q gain and 1p loss, are regarded as major prognostic factor in MM and their presence was shown to be associated with unfavourable disease course, although they often coexist with other genetic changes and amp1q21 alone was not showed to be an adverse prognostic factor in all studies. Methods We explored the prognostic value of amp1q21 alone and in coexistence with del17p13, del13q14 and t(4, 14) detected by fluorescence in situ hybridization (FISH) in newly diagnosed MM patients. The study was conducted in a cohort of 79 newly diagnosed MM patients upon the local Ethics Committee approval and according to guidelines of Declaration of Helsinki. All patients received first line regimens including thalidomide in a daily dose of 100 mg: 59 (75%) patients were treated with CTD (cyclophosphamide, thalidomide, dexamethasone) and 20 (25%) patients with MPT (melphalan, prednisone, thalidomide). Then 28 (35%) patients previously treated with CTD were given high-dose therapy with autologous stem cell support (HDT/ASCT). Results FISH analysis detected amp1q21 in 39 (49%), del13q14 in 38 (48%), t(4;14) in 16 (20%) and del17p13 in 13 (16%) patients. In 24 (30%) patients amp1q21 was combined with del13q14, in 12 (15%) with t(4;14) and in 5 (6%) with del17p13. The presence of amp1q21 correlated significantly with del13q14 and t(4;14). In the whole cohort of patients, the median PFS was 32.3 months in amp1q21-negative and 14.4 months in amp1q21-positive patients (p=0.049); the median OS was accordingly 40.0 and 26.2 months (p=0.027). In amp1q21-positive patients, the coexistence of additional aberrations made the outcome worse: del13q14 significantly shortened both PFS (22.8 vs 8.5 months, p=0.018) and OS (not reached vs 27 months, p=0.033), del17p13 significantly shortened OS (27.6 vs 11.5 months, p=0.048) and t(4;14) also significantly shortened OS (not reached vs 18.9 months, p=0.012). Moreover, analysis of patients with isolated amp1q21 showed that they have similar prognosis as amp1q21-negative patients (PFS not reached vs 22.7 months, p 〉 0.05 and OS not reached for both, p 〉 0.05). On the other hand, the amp1q21-positive patients with any of additional aberrations have significantly shortened survival: the median PFS of 8.5 months was significantly shortened in comparison both with amp1q21-negative patients (p=0.006) and with patients with isolated amp1q21 (p=0.018); the median OS of 16.7 months was significantly shortened in comparison with both of abovementioned groups (accordingly p=0.032 and p=0.033). The Kaplan-Meier estimates of PFS and OS are illustrated in Figure 1. Conclusions We demonstrate that isolated amp1q21 is not associated with poor prognosis in newly diagnosed MM patients treated with thalidomide. Our data clearly show that patients carrying amp1q21 accompanied by other genetic abnormalities, like del13q14, del17p13 or t(4;14), have significantly shortened PFS and OS than patients without amp1q21 or isolated amp1q21 and thalidomide-based regimens should not be recommended in this subset of patients. Acknowledgments The work was supported by a grant from the State Committee for Scientific Research, No. NN402287236.Figure 1Figure 1. Amp1q21-positive patients with additional aberrations had significantly shortened PFS and OS than amp1q21-negative patients (PFS: 8.5 months vs not reached, p=0.006: OS: 16.7 months vs not reached, p=0.032) and than patients with isolated amp1q21 (PFS: 8.5 vs 22.7 months, p=0.018; OS: 16.7 months vs not reached, p=0.033). The difference in PFS and OS between amp1q21-negative patients and patients with isolated amp1q21 was not statistically significant (p 〉 0.05 for both). Disclosures: Dmoszynska: Mundipharma: ; Roche: Honoraria.

Abstract: Background The relevance of differential splicing in human cancer is an evolving area of cancer biology. The recent findings of frequent mutations of the splicing pathways in MDS provide insight into the mechanism of alternative splicing, which has been long associated with the development of cancer. The genome-wide microarray analysis using Exon arrays discovered significantly differentially spliced genes in AML. Moreover, the AML specific "splicing profile" was normalized in remission and reappears with patient relapse, thereby supporting a role of deregulated splice variants in the process of leukemogenesis. A close cytogenetic and molecular analogy between de novo MDS and AML of elderly people suggests a common pathogenic mechanism for these conditions. Recent clinical and biological studies indicate that MDS and AML could be considered as part of the same continuous disease spectrum rather than as distinct disorders. Recently, we found that high expression of the NPM1 splice variant R2 may provide prognostic value for CN-AML patients. Assuming the common origin of MDS and AML we aimed to characterize the NPM1 R2 splice variant expression as well as the influence of R2 expression on NPM1 localization in groups with MDS, sAML and AML patients. Moreover, NPM1 stabilizes the ARF and interacts with the tumor suppressor p53, regulates the increase in stability and transcriptional activation of p53, thus contributing to modulating growth-suppressive pathways. Therefore, we characterized expression pattern of ARF, MDM2, TP53 genes with additional downstream molecules (p21, miR-34a) in AML, s-AML and MDS patients. Methods Since we found prognostic significance of the expression level of R2 for the AML cohort of patients, therefore we decided to evaluate its significance for MDS and sAML cases. For 61 samples (25 AML, 30 MDS and 6 samples with sAML) qRT-PCR was performed. Expression level of NPM1 R2 was assessed. To investigate whether R2 might disrupt localization of the NPM1 wild type protein, immunohistochemistry analysis for NPM1 in 23 AML bone marrow smears was performed. As NPM1 contributes to regulation of ARF-MDM2-p53-p21 signaling pathway proteins we assessed if high or low expression of its splice variant R2 might have influence on expression pattern of these transcripts. Results The expression of R2 was significantly higher in AML, s-AML and MDS groups compared to HVs (median 0.022 vs 0.005, p 〈 0.001, 0.022 vs 0.005, p 〈 0.001 and 0.015 vs 0.005, p 〈 0.001, respectively). The IHC stainings for AML samples revealed that in cases with high R2 expression we were able to determine a cytoplasmic localization of NPM1 even in the absence of its concomitant mutation. Therefore, we provide further evidence that the cytoplasmic localization of NPM1 might depend not only on its mutational status, but might be influenced by the distribution of its splice variants. We performed ARF, MDM2, TP53 and p21 mRNA expression analysis in AML, s-AML, MDS and HV groups and found significant differences between these groups (Figure 1A-D). We also analyzed the expression of ARF, MDM2, TP53 and p21 in groups with high or low R2 expression. We found elevated expression of MDM2 and TP53 in groups with high R2 expression in comparison to groups with low R2 expression in AML patients (median 0.007 vs 0.005, p=0.03 and 0.009 vs 0.005, p 〈 0.001, respectively), (Figure 1F, G). In case of MDS patients we also found elevated expression of MDM2 and TP53 in groups with high R2 expression compared to groups with low R2 expression (median 0.005 vs 0.003, p=0.033 and 0.006 vs 0.003, p=0.001, respectively), (Figure 1J, K). Conclusions In our study we found that the expression levels of R2 were elevated in AML, sAML and MDS groups compared to HVs suggesting that R2 might play some role in the process of the tumorigenesis not only in AML cases but also in early stages of development of this disease. As the NPM1 R2 splice variant represents a truncated form of NPM1 gene this isoform mostly localizes in the nucleoplasm, and thus might also have a biological impact in the malignant cells. We found elevated expression of MDM2 and TP53 in groups with high R2 expression compared to groups with low R2 expression in AML as well as MDS patients. In summary, the expression of NPM1 R2 might be of biological importance for AML as well as for sAML and MDS patients. This work was supported by National Centre for Science Grant HARMONIA (UMO-2013/10/M/NZ5/00313). Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract: Background Acute myelogenous leukemia (AML) represents a heterogeneous group of myeloid malignancies harboring different chromosomal abnormalities, gene mutations, and epigenetic modifications. Recent clinical and biological studies indicate that myelodysplastic syndromes (MDS) and AML could be considered as part of the same continuous disease spectrum rather than as distinct disorders. NPM1 is a multifunctional protein involved in both biological and pathological processes controlling development, cell proliferation, ribosome biogenesis, transformation and genomic stability. It interacts with many cellular proteins, including ARF and the tumor suppressor p53. Recently, we found that high expression of the NPM1 splice variant R2, which encodes a truncated form of NPM1, may provide prognostic value for CN-AML patients. Aims Therefore, our aim was evaluation of NPM1 R2 splice variant significance for MDS and sAML cases, as well as assignment if different expression levels of R2 might have influence on the expression pattern of each of the components of the ARF-MDM2-p53-p21 signaling pathway and additional downstream molecules (miR-34a, miR-34b and miR-34c). In order to determine the impact of NPM1 R2 on NPM1 localization and to compare it with the NPM1mut effect, transfection analyses and IHC stainings were performed. Methods NPM1 R2, CDKN2A (encoding ARF), MDM2, TP53 and CDKN1A(encoding p21) genes expression levels were assessed for 128 samples (58 AML, 62 MDS and 8 sAML) using qRT-PCR. Additionally, expression level of miR-34a (n=29), miR-34b (n=20) and miR-34c (n=20) was measured in CD33+ cells derived from AML patient samples. WI-38 fibroblasts and HEK-293 cells were transfected with constructs containing eGFP-tagged NPM1-R2, NPM1-mut and NPM1-wt under a cytomegalovirus promoter, stained and visualized with confocal microscope. Immunochemistry analysis was performed for NPM1 in 23 AML bone marrow smears. Results NPM1 R2 expression levels differed between AML, sAML, MDS and healthy volunteers (HV) groups and were significantly higher in AML, sAML and MDS groups compared to HVs (median 0.023 vs 0.005, p 〈 0.001, 0.025 vs 0.005, p 〈 0.001 and 0.017 vs 0.005, p 〈 0.001, respectively). CDKN2A, MDM2, TP53 and CDKN1A expression analysis in these sample groups showed also significant differences. Expression of TP53 was elevated in groups with high R2 expression in comparison to groups with low R2 expression in AML and MDS patients (median 0.01 vs 0.005, p 〈 0.001 and 0.007 vs 0.004, p 〈 0.001, respectively). Moreover, we found strong positive correlation of R2 expression with TP53 expression in AML (r=0.77, p 〈 0.001) and MDS (r=0.68, p 〈 0.001). We observed elevated expression of miR-34c in HVs group compared to AML (0.11 vs 0.07, p 〈 0,001) and trend to decreased expression of miR-34a in AML in comparison with HVs. No differences were found in miR-34a, miR-34b and miR-34c expression between groups with high or low R2 expression. Transfection analyses showed various localization of each eGFP-tagged NPM1 forms. NPM1-wt localized mainly in nucleoli, NPM1-R2 was detected in the nucleoplasm and nucleoli, whereas eGFP-NPM1-mut displayed cytoplasmic localization. However, the IHC stainings for AML samples revealed that in cases with high R2 expression we were able to determine a cytoplasmic localization of NPM1 even in the absence of its concomitant mutation. Conclusions The elevated level of NPM1 R2 splice variant in AML, sAML and MDS groups versus HVs suggests that R2 might play some role in neoplasia process also in early stages of this hematological malignancy. Transfection analyses established that NPM1 R2 mostly localizes in the nucleoplasm, where it might interact with other proteins e.g. ARF and p53. Nucleolar localization of this NPM1 form might be determined both by lack of nucleolar localization signal present in the wt form of NPM1 and nuclear export signal occurring in mutated NPM1. Moreover, strong positive correlation between R2 and TP53 expression was found in AML and MDS groups suggesting biological link between these transcripts. In summary, the expression of NPM1 R2 might be of biological importance for AML as well as for transformation of MDS into sAML. This work was supported by National Centre for Science Grant HARMONIA (UMO-2013/10/M/NZ5/00313). Disclosures Grzasko: Celgene: Honoraria; Munipharma: Honoraria; Janssen: Honoraria.

Abstract: Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis (MF). This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), representing MF disease from early (JAK inhibitor–naive) to late (JAK inhibitor–experienced) stages. Patients in the control arms (danazol in MOMENTUM, ruxolitinib in SIMPLIFY-1, and best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol (XAP). Across these studies, 725 patients with MF received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27% and grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% discontinuation rate). The incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, and hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in MF demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity. These trials were registered at www.clinicaltrials.gov as: MOMENTUM (#NCT04173494), SIMPLIFY-1 (#NCT01969838), SIMPLIFY-2 (#NCT02101268), and XAP (#NCT03441113).

Abstract: BACKGROUND: Recent EBMT analysis showed that infections are responsible for 21% of deaths after allo-HCT and 11% after auto-HCT. However, the risk, types and outcome of infections vary between age groups. The aim of the study is the direct comparison of risk factors of incidence and outcome of infections in children and adults. PATIENTS AND METHODS: We analyzed risk factors for the incidence and outcome of bacterial, fungal, and viral infections in 650 children and 3200 adults who received HCT between 2012-2015. The risk factors were determined by multivariable logistic regression analysis. RESULTS: A total number of 395/650 (60.8%) children and 1122/3200 (35.0%) adults were diagnosed for microbiologically confirmed infection, including 345/499 (69.1%) and 679/1070 (63.5%), respectively after allo-HCT, and 50/151 (33.1%) and 443/2130 (20.8%) respectively, after auto-HCT. At 2 years after HCT, the incidences of microbiologically documented bacterial infection were 36.0% and 27.6%, (p 〈 0.001) for children and adults, respectively. Incidences of proven/probable invasive fungal disease (IFD) were 8.4% and 3.7% (p 〈 0.001), respectively; and incidences of viral infection were 38.3%, and 13.5% (p 〈 0.001), respectively. Overall, 31/650 (4.8%) children and 206/3200 adults (6.4%) have died after these infections. The distribution of deaths was different in children (35.5% bacterial, 48.4% fungal, 16.1% viral) and adults (61.7% bacterial, 24.7% fungal, 13.6% viral). BACTERIAL INFECTIONS: In multivariable analysis, the risk of infections was higher after allo-HCT (HR=1.8; p 〈 0.001). In allo-HCT patients, the risk was higher in children (HR=2.1; p 〈 0.001), in patients with acute leukemia (HR=1.6; p 〈 0.001), matched unrelated (MUD) vs matched family-donor (MFD) HCT (HR=1.6; p 〈 0.001), mismatched unrelated (MMUD) vs MFD HCT (HR=2.0; p 〈 0.001), myeloablative vs reduced-intensity conditioning (RIC) (HR=1.3; p 〈 0.001), delayed ( 〉 21d) hematological recovery (HR=3.3; p 〈 0.001), acute GVHD before infection (HR=1.7; p 〈 0.001), and chronic GVHD before infection (HR=1.4; p=0.014). In auto-HCT patients, the risk was higher in children (HR=1.7; p 〈 0.001), and in patients with delayed hematological recovery (HR=2.8; p 〈 0.001). In patients with multiple myeloma (MM) the risk was decreased (HR=0.7; p=0.005). FUNGAL INFECTIONS: The risk of proven/probable IFD was higher after allo-HCT (HR=5.4; p 〈 0.001). In allo-HCT patients, the risk was higher in children (HR=3.9; p 〈 0.001), in patients with acute leukemia (HR=3.8; p 〈 0.001), MUD vs MFD HCT (HR=1.5; p=0.013), MMUD vs MFD HCT (HR=2.5; p 〈 0.001), delayed hematological recovery (HR=3.3; p 〈 0.001), acute GVHD before infection (HR=1.5; p=0.021), and chronic GVHD before infection (HR=2.2; p 〈 0.001). In auto-HCT patients, the risk was higher in children (HR=1.8; p=0.025). Patients with MM were at decreased risk of IFD (HR=0.6; p=0.005). VIRAL INFECTIONS: In multivariable analysis, the risk of infections was higher after allo-HCT (HR=6.1; p 〈 0.001). In allo-HCT patients, the risk was higher in children (HR=1.3; p=0.010), in patients with acute leukemia (HR=1.7; p 〈 0.001), MUD vs MFD HCT (HR=2.0; p 〈 0.001), MMUD vs MFD HCT (HR=3.3; p 〈 0.001), myeloablative vs RIC (HR=1.8; p=0.050), acute GVHD before infection (HR=1.5; p 〈 0.001) and chronic GVHD before infection (HR=2.7; p=0.014). Among auto-HCT patients, diagnosis of MM brought decreased risk of viral infections (HR=0.5; p 〈 0.001). DEATH FROM INFECTION: In allo-HCT patients, adults (HR=3.3; p 〈 0.001), recipients of MMUD-HCT (HR=3.8; p 〈 0.001), patients with acute leukemia (HR=1.5; p=0.023), chronic GVHD before infection (HR=3.6; p=0.014), CMV reactivation (HR=1.4; p=0.038) and with duration of infection treatment 〉 21 days (HR=1.4; p=0.038) were associated with increased risk of death from infection. Among patients with bacterial infections, the risk was higher in G- infections (HR=1.6; p=0.031). Among auto-HCT patients, no child died of infection. In adults, the risk of death was higher if duration of treatment of infection was 〉 21 days (HR=1.7; p 〈 0.001). In patients with MM the risk was decreased (HR=0.4; p 〈 0.001). CONCLUSIONS: The profile of infections and related deaths varies between children and adults. MMUD transplants, diagnosis of acute leukemia, chronic GVHD, CMV reactivation and prolonged infection are relative risk factors for death from infection after HCT. Disclosures Kalwak: Sanofi: Other: travel grants; medac: Other: travel grants.