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ABL1 Kinase Domain (ABL1-KD) mutations are a common resistance mechanism to tyrosine-kinase inhibitors (TKIs) in Chronic Myeloid Leukemia (CML) and Philadelphia Positive Acute Lymphoblastic Leukemia (ALL). Different ABL1-KD mutations induce different degrees of resistance to different TKIs. The early detection of these resistant mutations helps to adjust patient's treatment. Here we present an Ultra-Deep Sequencing approach to detect and quantify acquired ABL1-KD mutations in genomic DNA (gDNA), aiming to define a robust test to detect such alterations in TKIs exposed Philadelphia-Positive Leukemia Patients with a resolution below 1E-4. Firstly, we defined an ABL1 specific next-generation sequencing (NGS) panel designed to cover all coding regions of ABL1 exons 4-10. The 9 amplicons were designed to cover full exons where possible to detect co-occurring mutations (Figure 1A). A panel was then applied to 3 biological replicates of 3 Healthy control donors (9 NGS data points each with 220ng of gDNA). The average coverage per amplicon in all samples was at least 500,000x. The NGS data was then analyzed applying the NGS-MRD algorithm described elsewhere (Onecha, E et al. Haematologica 2019) to 25 known ABL1-KD hotspots. After applying our error correcting algorithm, we obtained an average of 135,000 (22,000-503,000) refined reads for the 25 hotspots. The limit of detection (LOD) was calculated for every position in the DNA as the mean noise (Variant Read Frequency; VRF) per position in the controls ± 3SD (standard deviation); the limit of quantification (LOQ) being defined as mean ± 10SD. For all the hotspots analyzed, the LOD was below 1E-4 and the LOQ below 3E-4 (Figure 1B), except for p.F311L (c.931T>C; LOD=2.7E-3). The high level of noise in this position, constant in the different control samples sequenced in different sequencing runs, is most likely related to the high number of homopolymers in the region. Ten Philadelphia-Positive Leukemia patients were then screened after TKI treatment (8 CML and 2 ALL). The median BCR-ABL1 defined by quantitative PCR (ratio BCR-ABL1 vs ABL1) in these follow-up samples was 0.6% (0.034% - 95%). All patients were screened in triplicates (220ng gDNA each) and the data-points ± 1SD from the mean were considered outliers (NGS false positives) and excluded from further analysis. Five patients presented a signal above the LOD for p.T315I (c.944C>T). This position is covered by 2 different amplicons in our panel. By bioinformatically demultiplexing the signal, the detection of those five mutations in both amplicons was confirmed (Amp_4; LOD=3E-5, Amp_5; LOD=4E-5). Moreover, aiming to validate this new approach, we applied to paired RNA samples an in-house BCR-ABL1/ABL1 nested PCR + NGS approach designed to quantify those alterations in cDNA. This approach confirmed the presence of 4 out of 5 gDNA detected mutations, with a Pearson correlation of 0.92 (Pval Here we show an Ultra-Deep NGS based test which allows the early detection of TKI resistant emerging clones in genomic DNA samples with a resolution of 1E-4. Despite the facts that in Phi-positive leukemia patients' other techniques such as the nested PCR are available, for most of heme- dyscrasias it is not easy to detect acquired mutations below 1% VRF. Our test can reduce this limit by at least 2 logarithms. The clinical impact of this approach is illustrated by the two LLA patients included, both under dasatinib therapy when the p.T315I mutations were detected. Those 2 patients were changed to ponatinib, reducing BCR-ABL1 levels. An extension of the cohort and the validation of our test at clinical level will be presented at the meeting. Figure Disclosures Heredia: Altum sequencing: Current Employment. Carrillo:Altum sequencing: Current Employment. Rufian:Altum sequencing: Current Employment. Wang:Hosea Precision Medical Technology Co., Ltd: Current Employment. Ribera:Pfizer, Amgen: Research Funding; Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau. Martinez-López:Janssen, BMS, Sanofi, Novartis, Incyte, F. Hoffmann-La Roche and Amgen: Honoraria, Other: Advisory boards; Hosea and Altum: Membership on an entity's Board of Directors or advisory committees; Janssen, Novartis, BMS, Incyte: Consultancy.

INTRODUCTION: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas classically treated with CHOP or CHOP-like regimens, with poor outcomes. CD30 is universally expressed and is pathognomonic in systemic anaplastic large cell lymphoma (sALCL), with variable expression among non-sALCL PTCL subtypes (40-60%). Recent data of frontline treatment with Brentuximab Vedotin (BV), an anti-CD30 monoclonal antibody, plus CHOP has demonstrated significant improvement in survival (ECHELON-2 clinical trial), becoming the new standard of care for sALCL in Europe. PATIENT AND METHODS: From February 2019 to April 2021, 21 patients with de novo newly diagnosed CD30+ PTCL have been treated with the combination of BV-CHP, in the centers of the Catalan Institute of Oncology in Spain. Survival curves were plotted by the Kaplan-Meier method. RESULTS: Clinical characteristics at diagnosis are shown in the table. Of interest, 5 of the 11 ALK negative ALCL patients were diagnosed of breast implant associated ALCL (BIA-ALCL) with extracapsular involvement. The number of cycles administrated were 108, with a median of 6 cycles per patient (range 1-6), all of them with G-CSF primary prophylaxis. At the time of this report, 1 patient was still on treatment and 2 patients without the final evaluation. Seven cycles (6%) were delayed (3 due to infection, 2 due to neutropenia grade 2, and 2 due to causes not related with chemotherapy).An adverse event was reported in 45 (44%) cycles, being the most frequent peripheral neuropathy in 14, nausea/vomiting in 9 and anemia in 8; all of them grade 1-2. Treatment was discontinued after 1 cycle in 1 patient due to progression. Of the 18 evaluable patients, the overall response rate (ORR) was of 83%, with 72% complete responses and 11% partial responses. Consolidative autologous stem cell transplant (ASCT) was performed in 5 patients. With a median follow-up of 14 months (limits: 1-24), 1-year progression-free survival (PFS) and overall survival (OS) was 68.2% (95% CI 44.6-91.7) and 82.2% (95% CI 63.9-100), respectively. CONCLUSIONS: Brentuximab Vedotin plus CHP is an effective regimen for CD30 positive PTCL, with a high rate of response. This combination presents a manageable safety profile, with the majority of patients completing the planned treatment. The incidence and severity of side effects are low, being peripheral neuropathy and neutropenia the most frequent. Figure 1 Figure 1. Disclosures Eva: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau. González-Barca: Janssen: Consultancy, Honoraria, Other: Travel; EUSA Pharma: Consultancy, Honoraria; Kyowa Kirin: Consultancy; Roche: Honoraria, Other: Travel; Takeda. Abbvie: Honoraria. Ribera: ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau. Sureda: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background and objective. Inotuzumab ozogamicin (InO) was approved for patients (pts) with relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL) based on the results of INO-VATE trial (Kantarjian et al, 2016). There are scarce studies evaluating the results of InO therapy in real life in similar pts as those from the INO-VATE trial. Our objective was to analyze the outcomes of pts included in the compassionate program of InO in Spain (June 2013-April 2018) before definitive approval. Patients and Methods. Inclusion criteria were age >18 yrs., CD22+ ALL, R/R resistant to ≥2 previous lines, Ph+ ALL resistant/intolerant to TKI, ECOG ≤2 or >2 if due to ALL, Bilirubin Results. 34 pts were included in the trial, 21 males, median age 43 yrs (range 19-73), ECOG 50% 15/33 (45%). 25/34 (73%) of pts received >2 previous lines of therapy and 20 (59%) were previously transplanted. The duration of first CR remission before InO was The median number of InO cycles was 2 (1-6). One pt withdrew the study before evaluation, 5 (15%) dead during therapy and 21 (64%) achieved CR/CRi. Ten pts (29%) were transplanted. With a median follow-up for alive patients after InO start of 26 months, the medians (95%CI) of DR, PFS and OS were 4.7 months (2.4-7.0), 3.5 (2.0-5.0) and 4.0 months (1.9-6.1), respectively. CR duration, PFS and OS were significantly shorter in refractory ALL (Figure 1A), pts with first CR (CR1) duration The most frequent adverse events were hepatic (24%), infectious (18%), hematologic (15%) and gastrointestinal (9%). 3/10 transplanted patients showed grade 3-4 VOD/SOS. Grade 5 toxic events were hepatic (n=2), infection (n=2) and hemorrhage (n=1). Conclusion. The results in this series of compassionate use of InO for R/R ALL before approval for clinical use were slightly inferior to that of the INO-VATE trial. However, patients form this series had poorer risk factors than those included in that trial. The frequency and type of AE were similar to that of observed in the INO-VATE trial. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Overall survival according to ALL status at inotuzumab start (A) and to duration of first complete remission (B) Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Hernández-Rivas: Celgene/BMS: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background The ongoing Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having an enormous impact on society worldwide and is especially posing a threat to health in vulnerable patients, such as patients with immune deficiencies. It is expected that patients who received Chimeric Antigen Receptor T-cell (CAR T-cell) therapy for hematologic malignancies are at risk for poor outcomes after COVID-19 due to their severely immunocompromised state caused by prior cumulative immunochemotherapy, on-target/off-tumor B-cell depletion, hypogammaglobulinemia and ongoing cytopenias. Current data are limited to small case series and case reports. This study describes the clinical characteristics and outcomes of CAR T-cell therapy recipients after developing COVID-19 in the largest cohort to date. Methods In response to the COVID-19 pandemic, the European Society for Blood and Marrow Transplantation (EBMT) developed a special COVID-19 report form to capture data from all patients with COVID-19 after treatment with CAR T-cell therapy for hematologic malignancies. Only PCR positive SARS-CoV-2 diagnosed patients before June 1 st, 2021 were included. The aim of this study was to describe the clinical course after COVID-19 diagnosis and evaluate overall survival. Overall survival probabilities were calculated using the Kaplan Meier method. Factors associated with mortality after COVID-19 diagnosis were examined using a Cox proportional hazard model. Results A total of 57 patients from 11 countries were reported to the EBMT. One patient with incomplete data at diagnosis and without any follow up information had to be excluded from the analysis. The median age of these 56 patients was 57.7 years (min-max 5.2 - 72.8) including 55 adults and one child. Of these patients, 32 were male. CAR T-cell therapy was given to 46 patients with B-cell-non-Hodgkin lymphoma, 7 patients with B-cell acute lymphoblastic leukemia, and 3 patients with multiple myeloma. The median time from CAR T-cell infusion to COVID-19 diagnosis was 7.4 months (min-max 0.03 - 25.3). At the time of COVID-19 diagnosis, 62.5% of patients were in complete remission, 12.5% of patients had a partial response and 25% of patients had relapsed/refractory disease. Forty-five patients (80%) were admitted to hospital (median 26,5 days, min-max 3-171) due to COVID-19. Of the admitted patients, 24 (53%) needed oxygen support. Twenty-two (49%) patients were admitted to the intensive care unit (median 14 days, min - max 2-65) and 16 (73%) of these patients received invasive ventilation. At the time of analysis, 25 of the 56 patients had died (44.6%), most (23/25) due to COVID-19, resulting in a COVID-19 attributable mortality rate of 41%. The Kaplan-Meier estimate of overall survival is shown in Figure 1. The median follow-up from COVID-19 diagnosis was 20.9 weeks. In 1 of the 32 alive patients there was no resolution of COVID-19 at the time of analysis. In multivariate analysis, older age (hazard ratio (HR) 1.50, 95% CI 1.11-2.03, p=0.009) and comorbidities (HR 2.56, 95% CI 1.05-6.23, p=0.001) had a negative impact on overall survival. Better performance status at time of admission (HR 0.72, 95% CI 0.59-0.88, p=0.038) had a positive impact on overall survival. Sex, time from CAR T-cell therapy to COVID-19 diagnosis, disease remission status and the occurrence of neurotoxicity or cytokine release syndrome after CAR T-cell infusion did not have a significant effect on overall survival in the multivariate analysis. Conclusion Patients with COVID-19 after B-cell-targeted CAR T-cell therapy have a very poor outcome. As it remains uncertain whether currently applied vaccination strategies against SARS-CoV-2 are effective after CAR T-cell therapy, vaccination of health-care personnel and family members in combination with protective measures against viral exposure are likely to play the most important role in protecting this vulnerable group of patients. Better treatment strategies are urgently needed. Figure 1 Figure 1. Disclosures Ljungman: OctaPharma: Other: DSMB; Enanta: Other: DSMB; Janssen: Other: Investigator; Takeda: Consultancy, Other: Endpoint committee, speaker; AiCuris: Consultancy; Merck: Other: Investigator, speaker. De La Camara: IQONE: Consultancy; Roche: Consultancy. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Barba: Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Sesques: Novartis: Honoraria; Chugai: Honoraria; Kite, a Gilead Company: Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Di Blasi: Kite, a Gilead Company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Thieblemont: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Nicholson: Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees; BMS/Celgene: Consultancy; Pfizer: Consultancy. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Ribera: NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Sanderson: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Bloor: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Ayuk: Novartis: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Gilead: Honoraria; Miltenyi Biomedicine: Honoraria; Celgene/BMS: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Kersten: Celgene: Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding. Mielke: DNA Prime SA: Speakers Bureau; Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; Miltenyi: Other: Data safety monitoring board; Gilead/KITE: Other: Travel support, Expert panel ; Celgene/BMS: Speakers Bureau.

Background: Genetic information has become critical to understand the development of T-cell acute lymphoblastic leukemia (T-ALL) and to elucidate the origin of disease relapse. Several genetic markers, together with measurable residual disease (MRD), are considered strong predictors of patient outcome. However, the prognostic significance of genetic markers can varie according to treatment. Aim: We used targeted deep sequencing to analyze the genetic profile of 125 T-ALL patients enrolled in three consecutive MRD-oriented trials from the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genomic information was analyzed together with the main clinical and biologic data in a subset of 111 patients with detailed clinical and outcome data to determine the prognostic significance for overall survival (OS) and cumulative incidence of relapse (CIR). Methods: Genetic mutations were detected using a custom gene panel and sequenced on a MiSeq platform. Alignment, variant calling, filtration and annotation of variants were done using standardized pipelines. OS curves were plotted by the Kaplan-Meier method and compared by the log-rank test. CIR was estimated using cumulative incidence functions by competing risks analysis. A Cox proportional hazard regression model was used to identify predictive factors for OS. Statistical significance was set at (two-sided) p-values Results: Recurrently mutated genes found in ≥4/125 patients involved transcription factor tumor suppressor genes (PTEN, BCL11B, RUNX1, GATA3, ETV6), epigenetic regulators (PHF6, DNMT3A, EP300, KMT2C, EZH2, TET2), DNA mismatch repair genes (MSH2), ribosomal (RPL5) and RNA splicing (U2AF1) genes, and genes involved in the RAS/MAPK (NRAS), WNT (FAT1, FAT3), IL7R-JAK-STAT (JAK3, JAK1, IL7R) and NOTCH1 signaling pathways, respectively. Mutations in the latest pathway (NOTCH1 & FBXW7) was found in 88/125 (70%) patients. Clinical-genetic correlations revealed that patients with mutations in JAK3, DNMT3A, N/KRAS, IL7R, MSH2 or in U2AF1 were associated with lower OS (vs unmutated patients). None of the mutated genes had impact on CIR. Upon grouping the mutated genes according to their functional role and potential biological impact on T-ALL, two gene signatures were defined. These included the aging gene signature (DNMT3A and U2AF1) characterized by mutations in genes identified in clonal hematopoiesis of indeterminate potential (CHIP); and the treatment resistance gene signature (JAK3, N/KRAS, IL7R and MSH2), defined by mutations in genes involved in resistance to the ALL therapy. Both clusters identified patients with poorer response to therapy (poorer blast clearance on day 14 of induction treatment and lower CR rates). Therefore, we considered together (worse outcome genetics [WOG] signature) for univariate and multivariate analyses. WOG and MRD level (0.1% cut-off) on day 35 after induction therapy (+35d MRD) showed significant prognostic impact in the univariable and multivariable analyses for OS (3y) with a hazard ratio (95% CI) of 2.4 (1.2; 4.8) and 2.7 (1.4; 5.1), respectively (Table 1). OS according to these two variables allowed risk stratification of T-ALL into low, intermediate- and high-risk (HR) patients with significantly different outcomes (p Conclusion: A genetic signature with independent prognostic significance of MRD has been identified in this cohort of patients included in MRD-oriented trials. This gene signature (WOG) together with MRD could help to improve risk-stratification of adult T-ALL patients and would be of interest in the search for new therapies for HR patients Funding: Support from AECC (GC16173697BIGA); ISCIII (PI19/01828 and PI19/01183), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future", CERCA/Generalitat de Catalunya SGR 2017 288 (GRC)/ C González-Gil was supported by AGAUR grant (2020 FI_B2 00210). Figure 1 Figure 1. Disclosures Diaz-Beyá: Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mercadal: Gilead Sciences, Inc.: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tormo: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Maciejewski: Regeneron: Consultancy; Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Alexion: Consultancy. Ribera: ARIAD: Consultancy, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau.

Background Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of HIV-associated lymphoma. Since the introduction of combined antiretroviral therapy (cART), the prognosis of HIV-related DLBCL has substantially improved, resembling that of the general population. However, non-Hodgkin lymphoma still remains the first cause of AIDS-related deaths. The International Prognostic Index (IPI) is the most widely used score for DLBCL and it has been validated in the rituximab era (R-IPI). However, it has limited accuracy to identify a very high-risk prognostic subset. Although IPI has been demonstrated to be useful for predicting prognosis in HIV-related DLBCL, new scores subsequently developed, such as National Cancer Comprehensive Network IPI (NCCN-IPI), GELTAMO-IPI and a new score, which includes data from peripheral blood count, have not been applied in the HIV setting. The aim of this study was to assess the prognostic significance of the new variables -beta2-microglobulin (β2M), lymphocyte/monocyte (L/M) ratio and red blood cell width (RDW)- and to validate the new scores in a series of homogeneously treated HIV-related DLBCL patients. Methods Retrospective multicentric study of patients with HIV infection diagnosed with DLBCL in 16 hospitals from GELTAMO group in Spain, from 1998 to 2020. All patients were treated with R-CHOP and cART +/- radiotherapy. The main clinical and biological variables were collected. Peripheral absolute neutrophil, lymphocyte and monocyte counts were studied, including L/M ratio and CD4 + lymphocyte count. Moreover, HIV load, serum lactate dehydrogenase (LDH), β2M and RDW were evaluated. Univariable and multivariable analysis were performed using the binary logistic regression model for complete response (CR) rate and Cox proportional-hazards regression model for overall survival (OS) and progression-free survival (PFS). Survival curves were plotted by the Kaplan-Meier method and compared by the log-rank test. The discrimination power of IPI, aaIPI (age-adjusted IPI), R-IPI, NCCN-IPI, GELTAMO-IPI and the new score including L/M ratio (L Bento et al., Br J Haematol. 2020) was assessed by the C-index. Results One hundred and five patients were retrospectively analysed with a median follow up of 7.08 (0.36-25.21) years. The characteristics of the patients are summarized in Table 1. In the univariable analysis, performance status ≥2, extranodal sites ≥2, lymphocytopenia and low L/M ratio were associated with shorter OS and shorter PFS probabilities. Neutropenia was also associated with lower OS and advanced Ann Arbor stage was associated with lower PFS. On the other hand, monocytosis, low CD4 + lymphocyte count, positive HIV load and high values of serum LDH, RDW and β2M had no prognostic impact. By multivariable analysis, only L/M ratio With the aim of validating the prognostic power of each score system, the patients were divided in two groups: patients corresponding with low or intermediate-low risk versus those with intermediate-high or high risk. R-IPI, NCCN-IPI and the new score including L/M ratio showed significant differences in two groups for CR rate, OS and PFS. IPI also significantly discriminated the groups for PFS. NCCN-IPI was the strongest score to discriminate OS with a C-index of 0.638, and the new score including L/M ratio was the best one for CR rate and PFS discrimination, with a C-index of 0.669 and 0.666 respectively. Conclusions Lymphocyte/monocyte ratio is a strong prognostic factor, which can be used in patients with DLBCL and HIV infection. NCCN-IPI and the new score including L/M ratio provided the best discriminative capacity to predict prognosis in patients with HIV-related DLBCL treated with R-CHOP and cART. Supported in part by Gilead Sciences S.L., Spain (GLD19/00121); 2017 SGR288 (GRE) from CERCA Programme/Generalitat de Catalunya, and by funds from Josep Carreras International Foundation and "la Caixa" Foundation. Figure 1 Figure 1. Disclosures Lopez-Guillermo: Roche, Gilead/Kite, Celgene, Novartis, Janssen, AbbVie, Spectrum: Consultancy, Honoraria, Research Funding. Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gilead: Research Funding. de la Cruz Vicente: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ferrer Lores: Janssen: Membership on an entity's Board of Directors or advisory committees. Abrisqueta: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau. Ribera: SHIRE: Consultancy, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Navarro: NOVARTIS, Roche: Honoraria; EUSA Pharma: Consultancy; GILEAD, EUSA Pharma: Research Funding.

Background and objective. The combination of HyperCVAD and ponatinib resulted in a high molecular response rate and survival in adults with Ph+ ALL, suggesting improved outcome compared with combinations of chemotherapy with first- or second-generation tyrosine kinase inhibitors (TKI) (Jabbour E, et al, Lancet Haematol. 2018;5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same chemotherapy as that of the ALL Ph08 trial that used imatinib as TKI (Ribera JM et al. Cancer 2019;125:2810-17). Final results of this trial are reported. Patients and method. PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin, prednisone) followed by consolidation (high-dose methotrexate, high-dose ARA-C, mercaptopurine, etoposide) and allogeneic hematopoietic stem cell transplantation (alloHSCT). Ponatinib was scheduled after alloHSCT only for patients (pts) with persistence/reappearance of MRD. Response to therapy (complete morphological [CR], molecular [complete -CMR- or major -MMR-] after induction and before alloHSCT) (assessed by centralized BCR-ABL1/ABL1 ratio), disease-free survival (DFS), overall survival [OS]) and toxicity were analyzed. The following genetic studies were performed: 1. Additional gene abnormalities (Copy Number Alteration [CNA] analysis by SNP array Affymetrix 750K), 2. ABL1 mutation status at diagnosis (Sanger sequencing), 3. T315I mutation at diagnosis (allele-specific PCR). A propensity score comparison with the results of the ALL Ph08 trial was performed. Results. Median age was 49 (19-59) years (y), and 13/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score was Among 7/16 pts without CMR after consolidation and genetic material available, 4 showed IKZF1 deletion (IKZF1 plus in 2), 1 showed CDKN2A/B and PAX5 deletion and 2 did not show any CNA. Among 5/19 pts with molecular relapse, 3 showed IKZF1 deletion (1 being IKZF1 plus), and 2 pts did not show any CNA. No ABL1 mutations or T315I mutation at diagnosis were found. Propensity score with 1:1 matching identified 30 pts in each cohort (variables: age, gender, ECOG, WBC, CNS involvement, cytogenetic risk and BCR/ABL isoform). 2y DFS rates for PONALFIL and ALL Ph08 trials were 97% and 62%, (p=0.005), and 2y OS rates were 97% and 66% (p=0.001) (Figure 2). 107 adverse events (AE) were registered in 20 pts (21 severe in 11 pts), prompting to withdrawn of the trial in 3 (thrombosis of central retina artery, severe bowel infection, grade IV hepatic toxicity). The most frequent AE were hematologic (28%), gastrointestinal (14%), hepatic (11%), infections (7%), and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina). Conclusions. The results of the PONALFIL trial show a high antileukemic efficacy with acceptable toxicity profile and compare favorably with the same chemotherapy schedule and imatinib. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. OS (A) and DFS (B). PONALFIL. Figure 2. OS (A) and DFS (B). PONALFIL vs. ALL Ph08. Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Esteve: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Novartis: Research Funding; Jazz: Consultancy; Astellas: Consultancy. Mercadal: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Speakers Bureau. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. OffLabel Disclosure: This trial includes Ponatinib in off-label indication.

Introduction and objective. SARS-CoV-2 pandemic has deeply impacted in Spain. In cancer patients (pts) the lethality has been higher than in normal population, but, little is known on the impact in adults with ALL. Our objective was to analyze the frequency, clinical characteristics and outcome of adult ALL patients infected by SARS-CoV-2. Methods. Between March 1, 2020 and May 31, 2020 (the period of the peak of COVID-19 infection in Spain) two registries from the PETHEMA (Programa Español de Tratamientos en Hematologia) and GETH (Grupo Español de Trasplante Hematopoyético y Terapia Celular) groups were activated to recruit adult patients with ALL and COVID-19 infection confirmed by PCR. The PETHEMA registry was based on ASH proposal (www.ashresearchcollaborative.org/covid-19-registry) and the GETH registry was specifically performed for hematological diseases and COVID-19 infection. Both registries were merged for this study. Eighty-four Spanish centers were contacted and weekly reminds were sent until May 19, 2020. The demographic and clinical characteristics of ALL and COVID-19 infection, the comorbidities, the treatment and outcome were collected. The study was closed for follow in July 10, 2020. Results. Fifty-six of 84 centers answered the survey and 28 patients with ALL and COVID-19 infection were identified in 17 of them, especially on March (n=11) and April (n=15). Median age was 46 (range 20-78) yrs. and 19 were aged over 40 yrs. Fifteen pts were male, 1 was active smoker and 9 showed one or more comorbidities (chronic liver disease [n=2] diabetes [n=1], hypertension [n=5], cardiopathy [n=2], prior malignancy [n=1] and hypogammaglobulinemia [n=1]). ALL was of B-cell precursors in 18 pts (Ph+ in 6) and T in 10. Twenty-six pts were on treatment of LAL (induction [n=10], consolidation [n=3], maintenance [n=1], HSCT [n=5], rescue [n=6], and palliative [n=1]). Eight patients were previously submitted to allogeneic HSCT, CAR T [n=1] or immunotherapy with monoclonal antibodies (inotuzumab, n=4) and 21 were receiving immunosuppressive drugs (corticosteroids in 11, fludarabine in 4, among others). Eleven pts showed neutropenia Conclusion. The frequency of adult patients with ALL and COVID-19 infection can be considered high, given the low incidence of adult ALL. COVID-19 infection was frequent in patients with advanced age and on ALL therapy. The frequency of severe COVID-19 infection and the mortality were high. Supported in part by 2017 SGR288 (GRC) Generalitat de Catalunya and "la Caixa" Foundation. Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis:Consultancy, Speakers Bureau;Pfizer, Amgen:Research Funding.Barba:Amgen, Celgene, Novartis, Pfizer:Speakers Bureau;Amgen, Celgene, Gilead, Jazz Pharmaceuticals, Novartis, Pfizer, Shire:Consultancy.

Introduction:Acute myeloid leukemia (AML) real-world incidence has been investigated in a limited number of European countries such as Sweden, Denmark and a few others. These prospective population-based analyses give a more precise idea of AML as a health problem than registry data from cooperative groups or other sources, that usually include selected cases as part of research studies and/or therapy trials. In October 2016, the Autonomous Government of Catalonia funded a project (PERIS SLT002/16/00433) to prospectively collect all AML cases from our territory. Objective:To investigate the incidence, characteristics and treatment decisions in all consecutive AML patients diagnosed in Catalonia between January 2017 and December 2019. Methods:Inclusion criteria were diagnosis of AML according the WHO 2016 criteria, both primary and secondary (APL excluded) with an age >18 years. The project was disseminated to all hospitals from Catalonia regardless of their size, having at least one hematologist. A specific informatics tool was implemented for remote reporting of the cases. All data were anonymized. In parallel, a circuit for centralized bio banking of patients' samples was designed. The database included the main clinical, laboratory data as well as the initial therapeutic approach. Cases included in our CETLAM group cooperative studies were automatically linked to the trial database for collecting detailed information. Statistical analyses were performed with R packages. Results:Assuming an incidence of AML of 4 cases per 100,000 inhabitants (based on previous reported data from others), we expected 912 cases during three years in the 7,6 million population of Catalonia. Our prospective registry included 750 consecutive AML patients, 82% of the expected cases. The remaining 18% could be explained by the exclusion of APL, age below 18 years, or underreporting. Seventy percent of patients (n=527) were diagnosed and treated in the 5 large University Hospitals from Barcelona and the two adjacent cities (Badalona and Hospitalet). Table 1 shows the main characteristics of the patients. Among the 390 patients up to 70 years, 272 (70%) were enrolled in the CETLAM AML-12 protocol that included intensive chemotherapy (ICT) and risk adapted hematopoietic cell transplantation (HCT). Forty-one additional patients (11%) in this age group received other ICT in different clinical trials. A remaining 73 patients (20%) were treated with other intensive or non-intensive approaches outside trials. In the group of 360 patients older than 70 years only a 33% (n= 119) were treated under the risk-adapted CETLAM AML-16 protocol for elderly AML patients. This trial included ICT as in the CETLAM-12 in case of favorable genetic features; this was received by 13 of the 119 patients (11%) enrolled. The remaining patients of CETLAM-16 were treated with low-intensity chemotherapy (oral fludarabine, subcutaneous (SC) cytarabine and G-CSF or azacytidine) and 97 additional elderly patients were included in other clinical trials mostly with targeted and hypomethylating agents (27%). Other active therapies outside trials (usually low-intensity) were administered in 50 additional patients (14%) whereas the remaining 94 patients (26%) only received supportive measures (transfusions, hydroxyurea, antibiotics, palliation, or no treatment), because of one or more of the following: advanced age, poor AML features or severe clinical condition. Overall survival (OS) of the whole series at 2 years was 31±2% (CI: 27-35). Patients younger than 70 years had a 2-year OS of 47±3% (CI: 41-53) compared to 11±3% (CI: 7-17) for those above 70 years (p Conclusions:This prospective study is highly representative of the diagnosis and treatment of AML in Catalonia. The median age at diagnosis was 70 years. Of note, 81% of patients up to 70 years were enrolled in ICT trials. The proportion of patients in trials in the elderly group was lower although still remarkable (60%). In this advanced age group, a 26% of patients were treated with supportive measures only. Despite the high inclusion rate in clinical trials, only one third of newly diagnosed AML patients have the probability to survive at 2 years, with a dismal outcome in those above 70 years. Therefore, the investigation of novel and more effective treatments remains mandatory. This series will be detailed and updated during the meeting. Disclosures Salamero: Pfizer:Consultancy;Jazz Pharmaceuticals:Consultancy, Honoraria;Daichii Sankyo:Honoraria;Novartis:Consultancy, Honoraria;Celgene:Consultancy, Honoraria.Olivera:BAYER:Consultancy;Pfizer:Consultancy, Speakers Bureau;Daiichi Sankyo:Consultancy, Speakers Bureau;Boehringer Ingelheim:Consultancy, Speakers Bureau.Sureda Balari:Celgene:Consultancy, Honoraria;Merck Sharpe and Dohme:Consultancy, Honoraria, Speakers Bureau;Sanofi:Consultancy, Honoraria;Novartis:Consultancy, Honoraria;Gilead/Kite:Consultancy, Honoraria;Janssen:Consultancy, Honoraria;Incyte:Consultancy;Roche:Honoraria;BMS:Speakers Bureau;Celgene/Bristol-Myers Squibb:Consultancy, Honoraria;Takeda:Consultancy, Honoraria, Speakers Bureau.Ribera:Pfizer, Amgen:Research Funding;Pfizer, Amgen, Ariad, Novartis:Consultancy, Speakers Bureau.Sierra:Jazz Pharmaceuticals:Research Funding;Pfizer:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Daiichi Sankyo:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead-Kite:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: The progress in the understanding of pathophysiology of AML has allowed the identification of genetic and immune abnormalities with prognostic impact on outcome and suitable as therapeutic targets. The genetic abnormalities are essential for risk allocation and risk-adapted treatment included the indication of hematopoietic cell transplantation. In the last decade, several studies have shown that persistence of measurable residual disease (MRD) after chemotherapy increases relapse incidence and the probability of leukemia recurrence and survival. Therefore, MRD has been progressively incorporated in prognosis estimation. In the last 25 years the CETLAM cooperative group has promoted 4 consecutive trials for AML patients fit for intensive chemotherapy and eventually HCT. Post-remission treatment was based on genetics of the disease and more recently on MRD. The aim of this study has been to investigate if the survival of patients has improved and, if so, to identify the factors that have influenced on the better outcome. METHODS: We included all patients with primary AML up to the age of 60 years enrolled in 4 consecutive Spanish CETLAM group trials. In brief, induction chemotherapy included idarubicin, cytarabine and etoposide in AML-94, AML-99 and AML-03 protocols and without etoposide in the AML-12. G-CSF priming was allowed in the two more recent trials. Post remission therapy included 1 to 3 consolidations including intermediate or high dose cytarabine. Hematopoietic transplantation indication was based on availability of an HLA-compatible donor, genetic findings and more recently MRD. Follow-up was extended to June 2020. The survival and relapse incidence analyses were censored at 5 years. Informed consent was obtained in all cases and the institutional review boards approved the protocols. RESULTS: Between 1994 and 2019, 1755 primary AML patients between 18 and 60 years-old fulfilled the inclusion criteria. The main characteristics of patients appear in table 1. Median age of the whole group was 46 years old. Overall survival (OS) in the whole group was 45% at 5 years, being significantly better in AML-03 and AML-12 than in AML-94 and AML-99 (image 1). Event free survival (EFS) in the whole group was 37% at 5 years, with also significant differences between trials. Also, the cumulative incidence of relapse (CIR) was 39% in the whole group with less relapses in the two more recent trials (image 2). To understand these findings, we analyzed first the CR rate over time that was higher in the AML-03 and AML-12 protocols (table 2). The results were different depending on genetics of AML with highest CR rate in patients with CBF AML and in those with intermediate-risk cytogenetics and favorable molecular findings; in contrast, patients with adverse cytogenetics had the lowest CR rate mainly because frequent refractoriness to therapy. According to outcomes in each MRC cytogenetic group 5y-OS was: 69±3% (63-76) in favorable group, 46±2% (43-49) in intermediate and 21±3% (16-27) in adverse group (p Referent to feasibility of allogeneic HCT, there was an increased access to the procedure over the years. A higher proportion of patients allografted in AML-03 and AML-12, 32% and 41% of patients in CR, respectively, compared to 16% in AML-94 and 19% in AML-99. A shortening of the interval between CR and transplantation has been observed in recent years; 3.9 months (mo) in AML-94, 2.7 mo in AML-99, 2.9 mo in AML-03 and 2.2 mo in AML-12. CONCLUSIONS: In adults with primary AML and age up to 60 years-old have improved over the last 25 years. During this period, the CETLAM group has refined the biological characterization of AML patients and tailored the post-remission therapy based on genetic markers with prognostic impact. The increased feasibility of allogeneic HCT may also justify the better results in more recent trials. Even though, there is substantial room for improvement, particularly in patients with AML and adverse genetic features. Disclosures Salamero: Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Daichii Sankyo: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Moraleda:Takeda: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Other: Travel Expenses; Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Ribera:Pfizer, Amgen: Research Funding; Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau. Sureda Balari:Roche: Honoraria; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Speakers Bureau; Celgene: Consultancy, Honoraria. Sierra:Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

Introduction and objective. Despite a high complete remission (CR) rate obtained with frontline therapy most adults with T-ALL eventually relapse. Although promising therapies are emerging, salvage options for T-ALL are currently limited. Little is known about outcome of patients (pts) with relapsed T-ALL (R T-ALL) treated with contemporary MRD-oriented trials. Our goal was to analyze the outcome of pts with R T-ALL included in two successive MRD-oriented trials (ALL-AR-03 and ALL-HR-11) from the Spanish PETHEMA Group. Methods. Retrospective study of R T-ALL adults diagnosed between 2003 and 2019 and included in the protocols ALL-AR-03 (NCT00853008) and ALL-HR-11 (NCT01540812). The clinical characteristics at baseline and at relapse, salvage therapies and outcomes (CR and OS) were analyzed and a study of prognostic factors for OS was performed. Results Forty-nine patients were identified (ALL-AR-03 [n=27], ALL-HR-11 [n=22]). Median age (range) at diagnosis was 29 (16-58) yrs, 38 males (78%), CNS involvement 6 (12%), mediastinal mass 30 (61%), WBC count 40.8 x109/L (0.6-351.0), early T-cell precursor 11 (23%), pre-T 8 (16%), cortical 16 (33%), mature 9 (18%), T unspecified 5 (10%). Post-induction-1 MRD level ≥0.1%: 14/42 (33%), ≥0.01%: 17/39 (44%). Nine pts (18%) required 2nd induction therapy (resistant disease after induction-1 [n=5], MRD≥0.1% after induction-1 [n=4]). Allogeneic HSCT in CR1: 8 pts. Interval CR1-relapse: 11.2 [0.1-36.7] months. Relapse was located in BM (n=20, 41%), BM+extramedullary (n=16, 33%) and extramedullary (n=13, 26%). CNS at relapse was involved in 18 pts (37%, isolated in 8 cases). Median number of rescue lineages was 2 (range 1-5). The most frequent first salvage schedules were FLAG-Ida (n=24, 49%), HyperCVAD (n=8, 16%) and nelarabine (n=4, 8%) (other schedules in 13 pts). Second CR was attained in 21/48 pts (44%). The patients with poor morphologic and/or poor MRD response after Induction-1 in first line therapy (n=9) did not respond to first salvage therapy (0/9 vs. 21/39, p=0.003). AlloHSCT was performed in 19 pts (15 in CR2) (HLA-identical sibling: 9, URD: 9, haploidentical: 1, myeloablative conditioning: 16). Thirty-nine pts died (progression: 27, toxicity of rescue regimens: 7, TRM: 5) and 9/10 alive patients were submitted to HSCT (the remaining is on rescue therapy). Median OS (95%CI) was 6.1 (4.9-7.2) months, 5yr OS probability 21% (9%-33%) (Figure 1). By multivariable analysis, only the CR after first salvage regimen emerged as favorable prognostic factor for OS (HR 3.110, 95%CI: 1.579-6.124) (Figure 2). Conclusion. This study shows poor outcome of adults with R T-ALL, with CR to first salvage therapy of 44% and a median OS of 6 months. Poor early response to first line therapy correlated with poor response to salvage-1. The only independent predictor for better survival was CR to first salvage regimen. This study highlights the unmet need for novel effective therapies for T-ALL. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation; ISCIII (PI19/01828), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future". Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Barba:Amgen, Celgene, Gilead, Jazz Pharmaceuticals, Novartis, Pfizer, Shire: Consultancy; Amgen, Celgene, Novartis, Pfizer: Speakers Bureau. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Giménez Conca:AbbVie: Honoraria, Speakers Bureau.