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[Background] Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca®) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46., [Methods] This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters., [Discussion] NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz’s capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression., We thank the Spanish Niemann-Pick Foundation for providing financial support. We also thank the Bellvitge University Hospital, IDIBELL and CERCA Program/Generalitat de Catalunya for institutional support.

We report the case of a 64-year-old woman with a mediastinal relapse of a uterine cervix cancer with positive human papillomavirus, an unusual site of recurrence. She consulted because of solid and liquid dysphagia of sudden appearance. Endoscopic study and non-contrast-enhanced CT showed intraluminal esophageal stenosis with a retrograde esophageal distension. 18F-FDG PET/CT demonstrated an infiltrating hypermetabolic lesion in posterior mediastinum, middle and lower esophagus, and stomach, with no signs of local or regional relapse of the uterine neoplasm.

Hepatocellular carcinoma (HCC) generally presents a low avidity for 2-deoxy-2-[18F]fluoro-d-glucose (FDG) in PET/CT although an increased FDG uptake seems to relate to more aggressive biological factors. To define the prognostic value of PET/CT with FDG in patients with an HCC scheduled for a tumor resection, forty-one patients were prospectively studied. The histological factors of a poor prognosis were determined and FDG uptake in the HCC lesions was analyzed semi-quantitatively (lean body mass-corrected standardized uptake value (SUL) and tumor-to-liver ratio (TLR) at different time points). The PET metabolic parameters were related to the histological characteristics of the resected tumors and to the evolution of patients. Microvascular invasion (MVI) and a poor grade of differentiation were significantly related to a worse prognosis. The SULpeak of the lesion 60 min post-FDG injection was the best parameter to predict MVI while the SULpeak of the TLR at 60 min was better for a poor differentiation. Moreover, the latter parameter was also the best preoperative variable available to predict any of these two histological factors. Patients with an increased TLRpeak60 presented a significantly higher incidence of poor prognostic factors than the rest (75% vs. 28.6%, p = 0.005) and a significantly higher incidence of recurrence at 12 months (38% vs. 0%, p = 0.014). Therefore, a semi-quantitative analysis of certain metabolic parameters on PET/CT can help identify, preoperatively, patients with histological factors of a poor prognosis, allowing an adjustment of the therapeutic strategy for those patients with a higher risk of an early recurrence.

Medullary thyroid carcinoma (MTC) is a rare malignancy. Location of residual, recurrent, or metastatic disease is crucial to treatment management and outcome. We aimed to evaluate the use of F-FDG PET/CT in localizing MTC foci in patients with biochemical relapse.This is a retrospective cohort study. Review of 51 FDG PET/CT studies of 45 patients referred to restage MTC due to increased calcitonin (Ctn) and carcinoembryonic antigen (CEA) values at follow-up. FDG PET/CT diagnostic accuracy was determined through a patient-based analysis, using histology as criterion standard when available, or other imaging studies and clinical follow-up otherwise (mean, 4 years).There were 25 positive scans. Sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and positive likelihood ratio were 66.7%, 83.3%, 88.0%, 57.7%, 72.5%, and 4.0, respectively. Using a Ctn cutoff of 1000 pg/mL, sensitivity increased to 76.9%. There were significant differences of Ctn and CEA values between positive and negative FDG PET/CT (P0.05). Regarding true-positive studies, average SUVmax comparing locoregional and metastatic disease was at the limit of significance (P = 0.046).PET/CT can be useful to restage patients with biochemical relapse of MTC, with a better performance in higher Ctn levels. Its high positive predictive value (88%) may impact in the therapeutic management, although its low negative predictive value (57.7%) makes strict follow-up mandatory in examinations without pathologic findings.

Chimeric antigen receptor T cells (CARTs) against CD19 antigen represent an effective therapy for relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL). There is no diagnostic test able to predict which patients with residual disease will relapse from those that will reach a delayed complete response. Positron emission tomography/computed tomography scan (PET-CT) is characterized by a significant number of false positive results after immunotherapy. Circulating tumor DNA (ctDNA) may be a good-useful tool to quantify minimal residual disease and for monitoring disease response.We present a patient with DLBCL treated with CART cells in which we tested the combined use of ctDNA and PET-CT scan.Disease reassessment with PET-CT scan showed a partial remission (3 weeks) and a very good partial remission (2 months). A clinical progression at 3 months was confirmed with PET-CT scan. Levels of ctDNA progressively decreased and became undetectable. An initial increase in KMT2D p.E4385G variant allele frequency confirmed disease progression.Our case shows how the complementary use of ctDNA and PET-CT scan could be a helpful tool in the clinical management of these patients.

Introduction: Asciminib is a new BCR-ABL1 inhibitor that differs from previous tyrosine kinase inhibitors (TKIs) in that it does not bind to the ATP-binding site of the kinase. Data from different clinical trials has shown an adequate safety and efficacy profile in chronic myeloid leukemia (CML) patients failing previous TKIs. However, no findings have been communicated in real life experience. The aim of our study is to present first results of asciminib in CML patients failing previous TKIs under the current compassionate use program. Methods: We retrospectively collected data from 31 patients treated with asciminib in 25 centers under compassionate use program. Data collecting was performed between October 2018 and June 2020. Patients baseline characteristics are shown in table 1. Most patients were heavily pretreated with 28 patients receiving 3 or more TKIs previous to asciminib. Eleven patients (35.5%) had been treated with ponatinib at some point throughout the disease. Twelve patients showed BCR-ABL1 mutations (only 1 case with T315I mutation). Switch to asciminib was due to intolerance in 22 patients and due to resistance in the remaining 9. Median dose of asciminib was 80mg per day (40mg every 12 hours). Treatment responses were evaluated according to European Leukemia Net recommendations. Data compilation and analysis were performed with REDCap Software and IBM SPSS (Version 25.0). Results: Median time on asciminib for the entire cohort was 35 weeks. Regarding toxicities, 13 patients (42%) experienced mild extra-hematological side effects (grade 1-2) being the most frequent fatigue (19%), joint pain (16%) and nausea (9%). Four patients (12,9%) showed severe (grade 3-4) extra-hematological events: fatigue, hepatotoxicity, hypertension and pericardial effusion (1 patient each). Three patients (9,7%) suffered from grade 4 thrombocytopenia, 2 of them associating grade 4 neutropenia. All toxicities according to previous TKIs adverse effects as well as cross-intolerance data is shown in table 2. Dose reduction had to be carried out in 9 patients (29%), 7 of those with temporary treatment interruptions; most owing to hematological adverse effects. In terms of efficacy (Graph 1), probability of reaching or at least maintaining previous response was 100%, 61.3% and 35.5% for complete hematological response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR), respectively. Regarding probabilities to improve previous responses, rates of CCyR and MMR were, respectively, 22,2% (2/9) and 22,2% (2/9) for resistant patients and 44% (4/9) and 62,5%. (10/16) for intolerant group. Amid the 11 patients previously treated with ponatinib, 3 patients (27,3%) showed improvement of response achieving at least MMR, 2 of them from the TKI-intolerant group and 1 from the TKI-resistant group. The median follow-up time was 40 weeks, after which 27 patients (87.1%) continued with asciminib. Treatment cessation happened in 2 patients due to progression to blastic phase and in 2 patients due to lack of efficacy. No patients discontinued due to side effects. Conclusion: The data presented, similar to that known from clinical trials, supports the use of asciminib in routine clinical practice in CML patients failing to previous TKIs. Disclosures Garcia-Gutiérrez: Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding.

An imaging case is presented on a patient referred to our department for an 18F-FDG-PET/CT, as a paraneoplastic syndrome was suspected due to his clinical situation. He had a history of acute myeloid leukemia (AML) treated two years earlier, with sustained complete remission to date. 18F-FDG-PET/CT findings revealed hypermetabolism in almost all nerve roots, suggesting meningeal spread, consistent with the subsequent MRI findings. Cerebrospinal fluid (CSF) findings confirmed a leptomeningeal reactivation of AML. Although not many studies have evaluated the role of 18F-FDG-PET/CT in leukemia, it is a noninvasive tool for detecting extramedullary sites of disease and a good imaging alternative for those patients on whom an MRI cannot be performed.

OBJECTIVE Somatic mutations in ASXL1 seem to have a negative prognostic impact in patients with several myeloid neoplasms, including myelofibrosis (MF). The aim of this work was to determine the prevalence and profile of ASXL1 mutations in MF. METHODS We analyzed mutations in ASXL1 in 70 consecutive MF patients from 8 Spanish hospitals by means of Sanger sequencing, as well as JAK2, CALR, and MPL mutations. RESULTS ASXL1 mutations were found in 16/70 (23%) of cases, most commonly p.Gly646TrpfsX12 (5/16). Most mutations (13/16) were frameshift mutations. Of 54 ASXL1- wild-type patients, 32 (59%) had at least one single nucleotide polymorphism (SNP), 27 of them had g.78128C>T, g.79017A>C, and g.79085T>C [triple SNP (TSNP) patients]. The 5-yr overall survival probability of TSNP patients was 67% (95% CI, 43-91%) vs. 90% (95% CI, 77-100%) in ASXL1-WT patients (P = 0.152). CONCLUSION ASXL1 mutations were found in 23% of cases, p.Gly646TrpfsX12 being the most frequent. About 85% of mutations were found only in individual cases and 46% had not previously been reported, a pattern also seen in other series. Fifty percent of ASXL1-WT patients had a combination of three specific SNPs that might have a prognostic correlation that needs to be determined in larger series.

Background: MCL is a heterogeneous disease and the existence of indolent clinical forms is increasingly recognized although their biological ground is not fully elucidated. The aim of this study was to propose a frontline tailored treatment for indolent clinical forms with a chemo-free regimen, ibrutinib in combination with rituximab. In addition, an extensive genomic study was associated to gain biological insight into these clinical forms. Methods: This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 14 Spanish GELTAMO sites (NCT02682641). Centralized histology, PET-CT review as well as minimal residual disease (MRD) studies (qPCR and NGS in peripheral blood [PB] and bone marrow [BM]) and biological studies are conducted. A total of 50 previously untreated MCL patients with indolent clinical forms are planned to be recruited, defined by the following criteria: no symptoms attributable to MCL, ECOG 0-1, stable disease without therapy need at least for 3 months, non-blastoid variants, Ki-67 Results: Forty patients (Gender M 29/ F 11; median age 65.7 years; low-risk MIPI 22% and intermediate/high MIPI 78%) were enrolled in the study up to data cut-off on 15 MAY 2019 (Consort diagram). The median observation time for the patients before treatment was of 7.6 months (range:3-107) and median follow-up was of 19 months. Efficacy data of the first 33 patients evaluable after 12 cycles of treatment are reported here, including two patients who were discontinued before cycle 12 due to related toxicity. A total of 27 patients achieved a response with an 82% overall response rate (ORR) and 75% CR. Among CR patients with evaluable MRD (N=23), the rate of undetectable MRD achieved after 12 cycles was 87%. Only 1 patient eventually became MRD positive at cycle 24, whereas 12 remained MRD negative and accordingly, nine of them discontinued ibrutinib as per protocol whereas 3 had interrupted treatment earlier because of intolerance. At data cut-off, all responding patients maintained the response with a median follow-up of 25 months (12-35). Only one patient progressed at one year of therapy. This particular case had shown intolerance to full-dose ibrutinib, received different salvage therapies and died of progressive disease. The estimated 15 month progression-free survival was 96% (CI95%: 89-100). Four patients withdrew the study because of serious adverse events, including cutaneous rash, severe aplastic anemia, pancreatic adenocarcinoma and lumbar fractures. Twenty-one additional G3 and G4 AEs related to Ibrutinib have been recorded including hematological toxicity in 7 patients, gastro-intestinal intolerance in 4 patients, arthralgias, atrial fibrillation and asthenia in one patient each. Conclusion: In indolent clinical forms of MCL frontline ibrutinib in combination with rituximab has a high efficacy, including undetectable MRD in the majority of cases, with a predictable toxicity profile. Figure Disclosures Gine: Roche: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Janssen: Other: Travel expenses, Research Funding. Martín:Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Teva: Research Funding; Roche: Consultancy, Honoraria, Other: Travel Expenses; Servier: Honoraria, Other: Travel Expenses; iQone: Consultancy; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Kiowa Kirin: Consultancy. Terol:Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy; Roche: Consultancy; Gilead: Research Funding; Abbvie: Consultancy. González-Barca:AbbVie: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Kiowa: Consultancy; Roche: Consultancy, Honoraria; Celtrion: Consultancy; Takeda: Honoraria. Lopez-Guillermo:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Background Treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML), who achieve a sustained and deep molecular response (DMR, MR4 or MR4.5) after treatment with BCR-ABL1 tyrosine kinase inhibitors (TKIs), is possible after TKI discontinuation (Rea and Cayuela. 2018). Nilotinib has been shown to elicit deeper and faster molecular responses compared to imatinib. More than 50% of patients who responded to imatinib, but did not achieve a DMR, achieved a DMR 1 year after they switched to nilotinib (Hughes et al. 2017). On attempting TFR, about 50% of patients lose response early and relapse (Mahon et al. 2019). The reason for this loss of response after achieving sustained DMR in patients has been attributed to residual and quiescent LSCs (Houshmand, et al. 2019). LSC for CML arises from the transformation of a hematopoietic stem cell through a t(9;22) translocation, leading to the Philadelphia chromosome [Ph1], and is characterized by the presence of the unregulated tyrosine kinase activity of the chimeric BCR-ABL1 protein together with specific surface antigens including CD26 and/or other aberrant markers (Bocchia, et al. 2018). The ENESTPath study is designed to evaluate the impact of duration of 24 or 36 months (mos) of consolidation treatment with nilotinib after switching from imatinib, on the rate of TFR. The LSC sub-study was designed to evaluate the correlation between duration of nilotinib therapy and LSCs. This interim analysis of the LSC sub-study presents preliminary data on characteristics of LSC-positive patients and their response after 24 mos of nilotinib therapy. Objectives To assess factors impacting LSCs and the effect of nilotinib therapy in patients with CML who switched from imatinib to nilotinib. Methods Patients from the ENESTPath study who switched from imatinib received 24 mos of nilotinib therapy (12 mos of induction and consolidation therapy, each). Patients who achieved stable MR4 (4/5 preceding quarterly real-time quantitative polymerase chain reaction [RT-PCR] assessments were ≥MR4 and last assessment was ≥MR4) at the end of the consolidation phase were randomized 1:1 to receive either an additional 1 year of nilotinib treatment or to start TFR, while those without stable MR4 were not randomized (NR), and followed-up until end of the study (5 years after baseline visit). For the current analysis, bone marrow samples collected at screening and at 24 mos were evaluated for the presence of Ph+ on fluorescence-activated cell sorting-purified CD34+CD38-/+ cells by fluorescence in situ hybridization and/or RT-PCR techniques. Results Of the 60 patients enrolled in the sub-study, 34 were randomized, 25 were NR, and 1 had protocol deviation (not included in the analysis). Overall, the mean age of the patients was 49.4 years. All patients had been previously treated with imatinib for a median duration of 59.7 mos. When analyzed for LSCs by RT-PCR or histone (HIS) at baseline, 10 patients were found to be positive, 23 were negative, 25 patients had data missing, and 1 was not evaluable. Sokal score categories and duration of prior imatinib therapy for LSC-positive and negative patients at baseline are presented in Table 1. More patients with low Sokal risk and longer duration of prior imatinib therapy (≥ 5 years) were negative for LSCs at baseline (Table 1). After treatment with nilotinib, the number of patients with Ph+ among CD34+CD38-, CD34+CD38+, and CD34+CD38-/+ LSCs was lower at 24 mos compared to baseline, except for aberrant CD34+ cells in the NR group (Figure 1). A decrease in the percentage of CD34+/CD38+ and immunophenotypically aberrant CD34+/- cells was observed for most of the patients analyzed at baseline and at 24 mos by HIS or RT-PCR. Overall, 11 and 10 patients in the randomized and NR groups, respectively, had ≥1 dose reduction/interruptions; adverse events led to dose reduction/interruptions in 9 patients each, in both arms. Conclusion This analysis indicates that treatment of CML patients with nilotinib after switching from imatinib may play a role in the reduction of LSCs over time. As the number of patients with available Sokal score at baseline and prior imatinib exposure was low, meaningful conclusions cannot be drawn, and further investigations are needed. Results of patients attempting TFR are awaited, and it would be interesting to analyze the correlation between the LSC count and rate of TFR in the final analysis of the sub-study. Disclosures Sanchez-Guijo: BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria. Plata:Novartis: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Caocci:Novartis: Honoraria; Celgene: Honoraria. Oakervee:Novartis: Honoraria; Bristol Myers-Squibb: Honoraria; Pfizer: Honoraria. Jedrzejczak:Amgen: Consultancy; Takeda: Consultancy; Novartis: Research Funding; Amgen: Other: Travel support for hematology meetings (ASH, EBMT, EHA) ; Celgene: Other: Travel support for hematology meetings (ASH, EBMT, EHA); Roche: Other: Travel support for hematology meetings (ASH, EBMT, EHA). Kiani:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Supekar:Novartis: Employment. Ferreira:Novartis: Employment. Shah:Novartis: Other: Service Provider. Steegmann:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy.

Resumen Objetivo Evaluar el papel de la positron emission tomography (PET, «tomografia por emision de positrones») combinada con la tomografia computarizada (TC) en la evaluacion inicial y valoracion de la respuesta en el linfoma cerebral primario (LCP). Material y metodo Se incluyeron 14 pacientes (8 varones), con una mediana de edad de 59,5 anos, diagnosticados de un LCP de novo . A todos ellos se les realizo una resonancia magnetica (RM) y una PET-TC cerebral en la evaluacion inicial. En 7 de ellos se realizo una PET-TC en la valoracion de la respuesta. Resultados La PET-TC en el momento del diagnostico mostro 31 focos hipermetabolicos, y la RM 47 lesiones, con un grado de concordancia bueno (k = 0,61; p = 0,005). En la valoracion de la respuesta, la correlacion entre ambas pruebas fue muy buena, siendo la PET-TC de ayuda en categorizar lesiones residuales de la RM. La supervivencia global a los 2 anos de los casos con PET-TC negativa frente a positiva fue de 100 y 37,5%, respectivamente (p = 0,045). Conclusiones La PET-TC es una tecnica util en la evaluacion inicial del LCP. Detecta menor numero de lesiones infracentimetricas que la RM, con una concordancia buena entre ambas pruebas. Es eficaz en la valoracion de lesiones residuales postratamiento. Son necesarios estudios prospectivos para confirmar su posible valor pronostico.

Objective To evaluate the role of positron emission tomography combined with computed tomography (PET-CT) in the initial evaluation and response assessment in primary central nervous system lymphoma (PCNSL). Material and method Fourteen patients (8 males) with a median age 59.5 years diagnosed of PCNSL. A brain PET-CT and magnetic resonance imaging (MRI) were performed in the initial evaluation. In 7 patients a PET-CT after treatment was performed. Results PET-CT showed at diagnosis 31 hypermetabolic focuses and MRI showed 47 lesions, with a good grade of concordance between both ( k = 0.61; p = 0.005). In the response assessment, correlation between both techniques was good, and PET-CT was helpful in the appreciation of residual MRI lesions. Overall survival at 2 years of negative vs. positive PET-CT at the end of treatment was 100 vs. 37.5%, respectively ( p = 0.045). Conclusions PET-CT can be useful in the initial evaluation of PCNSL, and especially in the assessment of response. Despite the fact that PET-CT detects less small lesions than MRI, a good correlation between MRI and PET-CT was observed. It is effective in the evaluation of residual lesions. Prospective studies are needed to confirm their possible prognostic value.

Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 109/l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 109/l (n = 29), patient's request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 (range, 6–25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP