Treatment-naïve Patients Research Articles

Real-World Efficacy of Venetoclax-Based Regimens in Patients with Chronic Lymphocytic Leukemia in Israel: A Multicenter Prospective Study

Real-World Efficacy of Venetoclax-Based Regimens in Patients with Chronic Lymphocytic Leukemia in Israel: A Multicenter Prospective Study

Humoral and Cellular Immunogenicity of COVID-19 Vaccinations in Patients with CLL

Humoral and cellular adaptive immunity likely contribute to protection against coronavirus disease 2019 (COVID-19). Neutralizing antibodies and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells have been detected in convalescent and immunized immunocompetent individuals. Chronic lymphocytic leukemia (CLL) and its treatment, particularly anti-CD20 monoclonal antibodies and Bruton tyrosine kinase inhibitors (BTKis), blunt the antibody response to vaccines. To understand the immunogenicity of COVID-19 vaccination in patients with CLL, assessment of the T-cell response is urgently needed.Between December 22, 2020 and May 7, 2021, 57 patients with CLL were immunized with either 2 doses of BNT162b2 (n = 30) or mRNA-1273 (n = 25) or 1 dose of Ad26.COV2.S (n = 2). Qualitative and semi-quantitative anti-spike antibodies were measured with serology tests authorized by the FDA under Emergency Use Authorization. A positive humoral response to vaccination was defined as the detection of anti-spike antibodies. Ultra-deep TCRß sequencing (Adaptive Biotechnologies) was performed on total peripheral blood mononuclear cells collected before and after vaccination. These data were analyzed in the immunoSEQ Analyzer. Differential abundance was calculated using the beta-binomial model and two-sided α=.05. SARS-CoV-2 spike-specific T cells were identified in the T-MAP COVID ImmuneCODE database. A positive cellular response to vaccination was defined as significant expansion of ≥1 spike-specific clonotype.Anti-spike antibodies were detected in 61% (35/57) of patients at a median (interquartile range, IQR) of 45 (30-56) days after the last dose of vaccine. The median (IQR) antibody titer was 19.1 U/mL (3.6-150.9) among 27 patients with humoral response. There were 4 patients with titers above the upper limit of quantification (>250 U/mL) and 4 patients who had qualitative testing only. The rate of humoral response was 71% (15/21) in treatment naïve (TN) patients, 57% (16/28) in patients treated with BTKi, and 0% (0/4) in patients treated with venetoclax and anti-CD20 monoclonal antibody (mAb). Among 16 BTKi-treated patients with anti-spike antibodies, 2 interrupted BTKi during the vaccination period. One patient treated with venetoclax monotherapy and 3 previously treated patients had detectable anti-spike antibodies. The immediate prior therapies were acalabrutinib >1 year before vaccination for 2 patients and chemoimmunotherapy >8 years before vaccination for 1 patient. Vaccination with mRNA-1273 induced numerically higher titers compared to BNT162b2 (median 85.5 U/mL versus 11.0 U/mL; P=.1), but the rate of seroconversion was not significantly different (P=.4). No patients reported a history of SARS-CoV-2 infection and anti-nucleocapsid antibodies were negative in 100% (50/50) of patients tested.Circulating CD8 + T cells increased from a median (IQR) of 13.2% (7.8-18.8) at baseline to 14.3% (8.8-20.6) after vaccination (P=.015). CD3 + and CD4 + T cells did not significantly change. TCRß sequencing results are available in 7 patients (Table). The median (IQR) number of productive templates, which corresponds to the number of T cells sequenced in each sample, was 447,805 (377,738-503,097). Cellular response was observed in 57% (4/7) of patients. A total of 10 expanded spike-specific clonotypes were identified and ranged between 1 and 6 clonotypes per patient. The cumulative frequency of spike-specific clonotypes after vaccination ranged between 0.0036% and 1.55% per patient. None of these clonotypes were found at baseline despite the large number of productive templates generated in each sample. Spike-specific T cells were detected in 50% (2/4) of patients with anti-spike antibodies and 67% (2/3) of patients without seroconversion.In conclusion, patients with CLL have impaired humoral and cellular responses to COVID-19 vaccination. Seroconversion occurred less often in patients treated with BTKi than TN patients and was absent in patients treated with venetoclax and anti-CD20 mAb. Cellular responses were seen in the absence of humoral responses. TCRß sequencing is ongoing in additional patients. Updated data will be presented at the meeting. [Display omitted] DisclosuresSun: Genmab: Research Funding. Wiestner: Merck: Research Funding; Nurix: Research Funding; Genmab: Research Funding; Verastem: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.

Effect of Bruton Tyrosine Kinase Inhibitor on Serologic and Cellular Immune Responses to Recombinant Zoster Vaccine

IntroductionThe recombinant zoster vaccine (RZV) is effective in preventing herpes zoster reactivation in the general population. We previously showed that patients with chronic lymphocytic leukemia (CLL), particularly those receiving Bruton tyrosine kinase inhibitors (BTKis), have decreased humoral immune responses following vaccination. The impact of vaccination on cellular immune responses in CLL patients is not well characterized. Understanding the effect of humoral and cellular immunity in CLL patients who are treatment naïve or receiving BTKis can inform vaccination strategies in this immunosuppressed patient population.MethodsIn this phase II open-label study (NCT03702231), patients with CLL who were either treatment naïve (TN) or receiving a BTKi (ibrutinib or acalabrutinib) received 2 doses of RZV via intramuscular injection at baseline and 3 months. Subjects were followed for 6 months and assessed for serologic response at 3 and 6 months. Serologic response was defined as a ≥ four-fold rise in anti-glycoprotein E (anti-gE) IgG serum titer at the 6 month timepoint. Cellular immune response was assessed by intracellular cytokine staining and flow cytometric analysis of gE-specific CD4+ T cells expressing upregulation of ≥2 effector molecules (interferon-γ, interleukin-2, tumor necrosis factor-α, and/or CD40 ligand). Cellular response was defined as ≥ two-fold rise over baseline and ≥320 net gE-specific CD4(2+) cells per million CD4+ T cells. Descriptive statistics were used to report vaccine response rates. Mann-Whitney test and Fisher's exact test were used to compare titers and response rates between different groups. Spearman r was used to measure the correlation between vaccine responses and clinical characteristics. All subjects completed an adverse event (AE) diary documenting any local (injection site) or systemic AE that started within 7 days after receiving the first and second vaccine dose.Results106 subjects had serologic response assessment at 6 months. Baseline characteristics are shown in Table 1. The serologic response rate to RZV was significantly higher in the TN cohort (76.8%, 95% CI, 64.2-85.9; n = 56) compared to patients receiving a BTKi (40.0%, 95% CI,27.6-53.8; n = 50; P = .0002). Cellular vaccine response was assessed in 94 subjects at 6 months. Similarly, the rate of cellular immunity was significantly higher in the TN cohort (69.4%, 95% CI,55.5-80.5; n = 49) compared to patients treated with a BTKi (40.0%, 95% CI,27.0-54.5; n = 45, P = .0067). Paired serologic and cellular responses were available in 93 subjects. 68.5% (95% CI,55.3-79.3; n = 54) of subjects with a serologic response also had a positive cellular immune response, whereas 35.9% (95% CI,22.7-51.6; n = 39) of subjects attained a cellular immune response in absence of a serologic response (P = .0029) (Figure 1). Among subjects with a negative serologic response and a positive cellular immune response, 42.9% were TN (n = 6) and 57.1% (n = 8) received a BTKi. There was no difference in serologic or cellular responses between patients treated with ibrutinib and acalabrutinib (P > 0.05). Serologic antibody titers and T cell responder frequencies were weakly positively correlated (r = 0.26; 95%CI .05-.44; P = .0127). Serologic titers and T cell responses were not correlated with age, beta-2 microglobulin, absolute lymphocyte count, absolute peripheral blood CD19+, CD3+, CD4+ or CD8+ counts or serum immunoglobulin levels (IgA, IgG, IgM) (all P > 0.05). The most frequent local and systemic AEs were injection site pain (98.3%), injection site reaction (97.4%), headache (51.7%), and generalized myalgias (51.7%). Most AEs were grade 1-2 and all AEs resolved or returned to baseline within 7 days of vaccine administration.ConclusionsRZV is safe in CLL patients and can induce both humoral and cellular immune responses. BTKi treatment was associated with impaired serologic and cellular vaccine responses compared to TN patients. Although BTKi therapy may inherently decrease vaccine immunogenicity, TN CLL patients could be more immunocompetent because of less advanced disease, thereby permitting more effective immune responses. The majority of patients with a positive antibody response also developed virus-specific T cells following vaccination. Approximately one third of patients without a positive serologic response developed virus reactive T cells. [Display omitted] DisclosuresLaing: Curevo Vaccine: Consultancy; MaxHealth LLC: Consultancy. Wiestner: Acerta Pharma: Research Funding; Pharmacyclics LLC: Research Funding; Merck: Research Funding; Nurix: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Koelle: Merck: Research Funding; Curevo Vaccine: Other: Scientific Advisory Board ; MaxHealth LLC: Other: Scientific Advisory Board ; Oxford Immunotec: Research Funding; Sensei Biotherapeutics: Research Funding; Sanofi Pasteur: Research Funding. Sun: Genmab: Research Funding.

Increased Neutrophil Aging Contributes to T Cell Immune Suppression by PD-L1 and Arginase-1 in HIV-1 Treatment Naïve Patients.

Neutrophils are characterized by their heterogeneity. They fight against pathogens and are involved in tissue injury repair and immune system regulation. Neutrophils have an extremely short life span in the peripheral blood and undergo aging after being released from the bone marrow. The over-aggregation of aged neutrophils is associated with phenotypical and functional changes. Here, we aimed to investigate the dynamics of neutrophil aging and its relationship with T cell exhaustion in HIV-1 infection, as they are not well understood. In this study, we enrolled 23 treatment naïve (TN) patients, 23 individuals that had received antiretroviral therapy (ART), and 21 healthy controls (HC). In these cohorts, we measured the degree of neutrophil aging, and its possible correlation with T cell dysfunction. In TN patients, peripheral neutrophils showed a more distinct aging phenotype and were over-activated compared to those in ART-treated patients. The degree of neutrophil aging was positively correlated with HIV-1 RNA viral load and negatively correlated with CD4+ T cell count. Moreover, aged neutrophils had impaired reactive oxygen species (ROS) production after lipopolysaccharide (LPS) stimulation, and were characterized by increased PD-L1 and arginase-1 expression in a time-dependent manner. Aged neutrophils demonstrated an increased inhibition of IFN-γ and TNF-α secretion by CD8+ T cell compared to non-aged neutrophils. The inhibition effect could be partially reversed by blocking PD-L1 and arginase-1 in vitro, and LPS was identified as an important activator of neutrophil aging. These results provide evidence that dampening neutrophil aging may provide a novel approach to recover T cell dysfunction in patients with HIV-1 infection.

Effectiveness, Durability, and Safety of Dolutegravir and Lamivudine Versus Dolutegravir, Lamivudine, and Abacavir in a Real-Life Cohort of HIV-Infected Adults.

Dolutegravir (DTG) plus lamivudine (2-DR) is suggested as an initial and switch option in HIV-1 treatment. To analyze the effectiveness, durability, and safety of 2-DR compared with DTG plus abacavir/lamivudine (3-DR). This was an observational, ambispective study that included all treatment-naïve (TN) and treatment-experienced (TE) patients who started 2-DR or 3-DR between July 1, 2018, and November 30, 2020. The primary end point was noninferiority, at 24 and 48 weeks, of 2-DR versus 3-DR regarding the percentage of patients with viral load (VL)≥50 and 200 copies/mL in TN (4% margin) and VL<50 and 200 copies/mL in TE (margin 12%). Durability of response, and safety were also measured. 242 patients were included (53 TN and 189 TE). Two TN patients on 2-DR had VL≥50 copies/mL and 1 had VL≥200 copies/mL at week 24. In TE patients on 2-DR, 90.2% achieved VL<200 copies/mL at week 24 (difference: 3.8%; 95% CI = -6.3% to 14%) and 91.8% at week 48 (difference: 0.06%; 95% CI = -9% to 10%), meeting noninferiority criteria. Among the 53 TN patients, only 1 VF was observed in 2-DR. In TN patients, the risk of treatment discontinuation was similar between groups (hazard ratio [HR] = 0.37; P = 0.15); similar rates were also found in TE patients (HR = 0.94; P = 0.85). TE patients on 2-DR showed a better safety profile compared with 3-DR patients (P<0.001). Our results did not show noninferiority in terms of virological effectiveness. Nevertheless, all effectiveness measures support the use of 2-DR in a real-life cohort of TN and TE. Additionally, durability and safety of 2-DR were confirmed to be similar to that of 3-DR.

Risk Factors for Grade 3/4 Transaminase Elevation in Patients with Chronic Lymphocytic Leukemia Treated with Idelalisib

Introduction: Idelalisib (IDELA) is a selective PI3Kδ inhibitor approved for use with rituximab in patients with previously treated chronic lymphocytic leukemia (CLL). Reversible transaminase elevation (TAE) has been observed in all CLL clinical trials involving IDELA, with frequencies of Gr ≥3 elevation in company sponsored Ph 2 and 3 studies utilizing the approved dose of 150 mg orally twice a day, ranging broadly from approximately 10% (Sharman ASH 2014) to 41% (Hillmen EHA 2017). TAE leads to permanent discontinuation of IDELA in approximately 3% of patients (Coutre EHA 2015). Risk factors for Gr ≥3 TAE are not well understood. Lampson et al. (Blood 2016) reported a trend toward increased risk in younger patients and those with mutated IGHV in a series of 24 previously untreated CLL patients who received IDELA monotherapy. In the present study, we analyze the rates of Gr ≥3 TAE across all fully enrolled, Gilead sponsored Ph 2 and 3 studies with the goal of identifying risk factors related to patient and treatment characteristics and selected CLL genetic alterations. Methods: Data were reviewed from patients who received at least 1 dose of IDELA in any of 6 Ph 2 or 3 studies, 3 for treatment naive (TN) and 3 for relapsed/refractory (R/R) CLL. The following variables were used for analysis: age, prior therapy (Y vs N), combination with bendamustine plus rituximab (BR; Y vs N), del(17p) (Y vs N), and IGHV mutated vs unmutated. Results: A total of 853 patients were enrolled and treated with IDELA (Table 1) and comprise the safety analysis set (SAS). The median age was 67 y (range: 37-90), and the median IDELA exposure time was 11 mo (range: Conclusions: In this ad hoc analysis of 853 patients treated in Gilead sponsored trials of IDELA, younger age and TN status were risk factors for developing Gr ≥3 elevation of hepatic transaminases, as was treatment with BR for patients with R/R CLL. The highest incidence of Gr ≥3 TAE was observed in a single-arm trial of previously untreated patients with del(17p). IGHV mutation status was not a significant risk factor in this dataset. A statistical model of risk factors for Gr ≥3 TAE will be presented, considering interactions between the factors. Disclosures Brown: Infinity Pharmaceuticals: Consultancy; Pharmacyclics: Consultancy; Sun BioPharma: Consultancy, Research Funding; Astellas Pharma: Consultancy; Redx: Consultancy; Janssen: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Honoraria; Roche/Genentech: Consultancy; Janssen Oncology: Honoraria; Gilead: Consultancy, Research Funding; Pfizer: Consultancy; AstraZeneca: Consultancy. Zelenetz: Genentech Roche: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Mei Pharma: Research Funding; Hospira: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria. Furman: TG Therapeutics: Consultancy; Verstem: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy, Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; Genentech: Consultancy. Lamanna: Gilead: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Mato: DTRM: Research Funding; Pharmacyclics: Research Funding; Portola: Research Funding; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity9s Board of Directors or advisory committees; Kite: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; TG Therapeutics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Regeneron: Research Funding; AbbVie: Consultancy, Research Funding. Montillo: Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Roche: Research Funding; Novartis: Honoraria; Genetech: Research Funding. O9Brien: CLL Global Research Foundation: Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Alexion: Consultancy; Acerta: Other: Research Support: Honorarium, Research Funding; GSK: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Vaniam Group LLC: Consultancy; AbbVie: Consultancy; ProNAI: Other: Research Support: Honorarium, Research Funding; Celgene: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Sunesis: Consultancy; Astellas: Consultancy; Aptose Biosciences, Inc.: Consultancy. Dreiling: Gilead Sciences, Inc.: Employment. Dubowy: Gilead Sciences, Inc.: Employment, Equity Ownership. Kim: Gilead Sciences, Inc.: Employment. Munugalavada: Gilead Sciences, Inc.: Employment, Equity Ownership. Robak: Janssen: Consultancy, Honoraria, Research Funding; Akari Therapeutics Plc: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Hillmen: Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Research Funding.

Single-Agent Ibrutinib Versus Real-World Treatments for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia: Adjusted Comparison of Resonate-2™ with Real-World Databases

Single-Agent Ibrutinib Versus Real-World Treatments for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia: Adjusted Comparison of Resonate-2™ with Real-World Databases

Initial Results of the Phase 2 Treatment Naive Cohort in a Phase 1b/2 Study of Obinutuzumab, Ibrutinib, and Venetoclax in Chronic Lymphocytic Leukemia

BACKGROUNDVenetoclax (VEN), a once daily oral inhibitor of BCL2, achieves high response rates and acceptable toxicity in patients with relapsed or refractory (R/R) and treatment naïve (TN) CLL both as a single agent and in combination with anti-CD20 monoclonal antibodies such as obinutuzumab (OBIN), where minimal residual disease (MRD) negative responses have been observed in the majority of patients. Pre-clinical data suggest that concurrent treatment with the Bruton tyrosine kinase inhibitor ibrutinib (IBR) may further potentiate sensitivity to VEN. Given high individual response rates, largely non-overlapping toxicity, and distinct mechanisms of action, we initiated a phase 1b/2 study of combination OBIN, IBR, and VEN in CLL. A phase 1b study in R/R CLL patients established VEN 400mg daily as a safe dose for use in this combination. We report the initial results from the phase 2 cohort of TN patients.METHODSPatients with TN, symptomatic CLL meeting IWCLL 2008 guideline indications for therapy were eligible. Eligible patients had an ECOG PS ≤1 and preserved end-organ function, including creatinine clearance ≥50 mL/min/m2. Patients with chronic viral hepatitis infection, uncontrolled autoimmune cytopenia, and/or clinically apparent Richter's Transformation were excluded. Treatment was given at the doses and schedule established in the preceding phase 1b study (Jones ASH 2016). Treatment was planned for 14 cycles (C) of 28 days each with OBIN, IBR, and VEN started sequentially over the first 3 cycles. OBIN was started C1 (C1 D1: 100mg, C1 D2: 900mg, C1 D8,D15: 1,000mg, C2-8 D1: 1,000mg), IBR in C2 (C2-14 D1-28: 420mg), and VEN in C3 with dose escalation according to its US label (C3 20mg->50mg->100mg->200mg, C4-14 D1-28: 400mg). Risk for tumor lysis syndrome (TLS) with VEN was assessed according to US prescribing information. Adverse events (AEs) were assessed and graded using the NCI CTCAE v4.03 except hematologic AEs which were graded according to the IWCLL 2008 guidelines. Response was determined according to IWCLL 2008 criteria after cycles 8 and 14 with assessment for MRD in the bone marrow and peripheral blood by standard 4-color flow cytometry.RESULTSEnrollment was completed in November 2016 with 25 TN patients. The median age at enrollment was 59 (range 24-77) and 15 (60%) patients were men. Baseline risk characteristics included unmutated IGHV in 17 (71%) patients, complex karyotype in 6 (24%), FISH positive for del(17p) in 3 (12%), del(11q) in 5 (20%), del(13q) in 7 (28%), and tri(12) in 4 (16%). TLS risk was high for 7 (28%) and medium for 18 (72%) patients. In general, AEs were consistent with reports from the phase 1b study in R/R patients and the known safety profile of the individual agents. The most commonly experienced grade 1/2 treatment-related AEs were infusion reactions (76%), nausea (60%), and dyspepsia (52%). The most common grade 3/4 treatment-related AEs were neutropenia (44%), leukopenia (36%), thrombocytopenia (36%), lymphopenia (32%), and hypertension (20%). Hematologic toxicities were the most frequent high grade treatment-related AEs. There were no cases of neutropenic fever or TLS. Treatment-related AEs are in Table 1. To date 23 patients have reached the first (post-C8) response assessment with 1 patient leaving the study prior to C8 and 1 not yet reaching this time point. Of these 23 patients all had an objective response. The rate of complete remission (CR), including with incomplete marrow recovery (CRi), was 50% (12/24). MRD-negative status by flow cytometry in both blood and bone marrow was achieved in 14 (58%) patients; 3 CR, 5 CRi, 6 partial remission (PR). Responses at this early time point are summarized in Table 2. Twenty-two patients remain on study with 1 patient discontinuing treatment after C7 at the discretion of the treating physician, 1 patient after C10 electively, and 1 patient after C10 for the serious AEs of grade 3 colitis as well as grade 4 neutropenia which were both possibly related to study treatment.CONCLUSIONSOBIN, IBR, and VEN can be given safely without TLS and appears highly effective as initial therapy for CLL after response assessment at this initial (C8) time point. Objective responses, including MRD-negative complete responses, have been achieved in all patients to date and results for the primary endpoint of MRD (-) CR after C14 are expected in May 2018. Updated toxicity and response data will be presented for the 22 of 25 patients who remain on study. [Display omitted] DisclosuresMaddocks:Novartis: Research Funding; BMS: Research Funding; Pharmacylics: Research Funding; Merck: Research Funding.

Compromised long-lived memory CD8+ T cells are associated with reduced IL-7 responsiveness in HIV-infected immunological nonresponders.

Immune deficiency is one of the hallmarks of HIV infection and a major cause of adverse outcomes in people living with HIV (PLWH). Long-lived memory CD8+ T cells (LLMCs) are essential executors of long-term protective immunity; however, the generation and maintenance of LLMCs during chronic HIV infection are not well understood. In the present study, we analyzed circulating LLMCs in healthy controls (HCs) and PLWH with different disease statuses, including treatment naïve patients (TNs), complete responders (CRs), and immunological nonresponders (INRs). We found that both TNs and INRs showed severely compromised LLMCs compared with HCs and CRs, respectively. The decrease of LLMCs in TNs correlated positively with the reduction of their precursors, namely memory precursor effector T cells (MPECs), which might be associated with elevated pro-inflammatory cytokines. Strikingly, INRs showed an accumulation of MPECs, which exhibited diminished responsiveness to interleukin 7 (IL-7), thereby indicating abrogated differentiation into LLMCs. Moreover, in vitro studies showed that treatment with dexamethasone could improve the IL7-phosphorylated (p)-signal transducer and activator of transcription (STAT5) response by upregulating the expression of the interleukin 7 receptor (IL-7Rα) on MPECs in INRs. These findings provide insights that will encourage the development of novel therapeutics to improve immune function in PLWH.

Ibrutinib and Obinutuzumab in CLL: MRD Responses Sustained for Several Years with Deepest MRD Depletion in Patients with >1 Year Prior Ibrutinib Exposure

Ibrutinib and Obinutuzumab in CLL: MRD Responses Sustained for Several Years with Deepest MRD Depletion in Patients with >1 Year Prior Ibrutinib Exposure

Earlier Use of Zanubrutinib Monotherapy in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Is Associated with Greater Efficacy: A Pooled Analysis from 3 Studies

Earlier Use of Zanubrutinib Monotherapy in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Is Associated with Greater Efficacy: A Pooled Analysis from 3 Studies

Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma and del(17p): Arm D of the SEQUOIA (BGB-3111-304) Trial

Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma and del(17p): Arm D of the SEQUOIA (BGB-3111-304) Trial

Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide

AbstractSevere aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naïve (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805.

The Path to Cure: Using Haploidentical (haplo) Donors and High-Dose Post-Transplant Cyclophosphamide (PTCy) for Treatment-Naïve and Refractory Severe Aplastic Anemia (SAA)

SAA is a life-threatening hematopoietic stem cell disorder that is often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis and eliminate clonality. Our group has shown that PTCy after related HLA-haplo BMT can facilitate engraftment and yield low rates of relapsed and refractory (R/R) SAA. Given the risk of relapse or secondary clonal disease following immunosuppressive therapy (IST) is &amp;gt; 50% at five years, we decided to implement this treatment paradigm in untreated SAA. Here, we review the haplo outcomes in SAA, with an update in R/R SAA patients and new results in treatment-naïve (TN) SAA patients using haplo donors and PTCy. Patients were eligible with SAA. Fanconi anemia and short telomere patients were excluded. R/R patients had ≥ one course of IST. The conditioning regimen included standard published haplo backbone of antithymocyte globulin, low dose CY, and total body irradiation (TBI). All R/R patients received 200cGy. The TBI dose for the TN cohort was modified after 3 graft failures (GF) in initial 7 patients treated at 200cGy; thus, the last 8 TN patients received 400cGy. After the marrow graft was infused on day 0, cyclophosphamide 50mg/kg/day IV on days +3,+4 post-transplant was administered. All received mycophenolate mofetil beginning day +5 through 35 and tacrolimus day +5 to 365. Engraftment definitions include: absolute neutrophil count &amp;gt;1.0 x10E9/L for three consecutive days; days from last red blood cell transfusion for hemoglobin and platelet count &amp;gt;50,000 for 7 days without transfusion. Thirty-five SAA patients received haplo BMT: 20 R/R and 15 TN. The median follow-up is 31 months (90% CI: 26.0, 45.4). The median age was 25 (range, 4-69) years, with 23 patients &amp;gt; age 20 and 57% were males. The median related haplo donor age was 34 years (range, 19-57), including three non-first degree relatives. Table 1 shows data by cohort. Median time to neutrophil recovery was 17 days (range 15-88), to red cell recovery 23 days (range 6-58) and to platelet recovery 28 days (range 15-108). At the time of BMT, 25 of 35 patients had evidence of clonality (mostly PNH clones). Four of 35 patients (11.4%) (95% CI: 3.2, 26.7%) experienced GF. There was one GF out of 20 patients in the R/R group (5%) (95% CI: 0.1, 24.9%) and 3 of 15 in the TN group 20% (95% CI: 4.3,48.1%, p= 0.20). OS for all patients (Figure 1) is 94% (90% CI: 88,100%) at one and two years, 100% in the R/R group and 86% (90% CI: 72, 100%) in the TN group. The cumulative incidence of grade II-IV aGVHD at day 100 is 9% (90% CI: 1, 17%). The cumulative incidence of chronic GVHD at 2 years is 9% (90% CI: 1,17%). All R/R patients are alive and well, and fully engrafted with 100% donor chimerism; patient with primary GF is 100% chimeric after 2nd transplant from different haplo donor. One patient has extensive cGVHD. Of the first 7 TN patients who received 200cGy TBI, 4 are fully engrafted and well; of the 3 with GF, 2 died from infection and one is now 100% chimeric using second haplo donor. After increasing the TBI dose to 400cGy, the subsequent 8 patients are alive with full donor chimerism. Nonmyeloablative haplo BMT with PTCy represents a potential cure in SAA, with all 20 R/R currently alive, disease-free (including eradication of clonal diseases), and no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates. Perhaps this is not surprising given that the potential beneficial effect of front-line IST on engraftment is absent. The increase in TBI dose to 400cGy in TN patients appears to achieve more durable engraftment without early greater toxicity (infection, delayed engraftment, GVHD); more patients and longer follow up are required to understand rates of fertility and other survivorship issues. Alternative donor BMT (including haplo donors) should be offered to all SAA patients with R/R SAA who are fit enough to tolerate non-myeloablative conditioning. A potential advantage of haplo donors over unrelated donors is that the transplant center has full control and oversight of allograft quality, which can be especially important with the use of the preferred allograft source for SAA, bone marrow. Non-myeloablative haplo BMT in TN SAA could lead to a paradigm-shift in the field, such that essentially all children and fit adults can proceed quickly to a relatively safe, curative BMT. Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Cooke:Jazz pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Final Results of Prospective Treatment with Pegylated Interferon Alfa-2a for Patients with Polycythemia Vera and Essential Thrombocythemia in First and Second-Line Settings

Final Results of Prospective Treatment with Pegylated Interferon Alfa-2a for Patients with Polycythemia Vera and Essential Thrombocythemia in First and Second-Line Settings

HSR19-084: Real-World Treatment Patterns and Clinical Outcomes in Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations

Background: Mutations in the epidermal growth factor receptor (EGFR) gene have been identified in 10%–50% of patients with non-small cell lung cancer (NSCLC). Exon 20 insertion mutations represent about 2%–10% of this group. Reports of real world experience of NSCLC patients with EGFR exon 20 insertion mutations are limited. This study describes patient characteristics, treatment patterns, and survival outcomes of NSCLC patients with EGFR exon 20 insertions based on real world data. Methods: Flatiron Health electronic health record data, largely from community oncology practices, from January 2011–April 2018 were used for this retrospective observational study. Treatment-naïve (TN) and relapsed/refractory (RR) second-line patients diagnosed with NSCLC with EGFR exon 20 insertion mutation aged ≥18 years at treatment initiation were included. Patient characteristics were described, and Kaplan-Meier analyses were used to assess real world overall survival (rwOS) separately for TN (starting at first-line therapy) and RR (starting at second-line therapy) patients. Results: There were 128 TN and 71 RR patients identified. Median age was 66.5 and 65.0 years for TN and RR patients, respectively, and over half were female (TN: 59.4%, RR: 53.5%). Among 83 TN and 47 RR patients with known ECOG score at advanced diagnosis, most had score 0–1 (TN: 56.3%; RR: 62.0%). Central nervous system metastases were observed in 35.2% of TN and 33.8% of RR patients. While 45.3% of TN patients received any chemotherapy, approximately 20% of both TN and RR patient groups had exposure to various EGFR TKIs. Overall, median rwOS was low at 14.6 months for TN patients, and 10.1 months for RR patients. Conclusion: Real world survival of patients with EGFR exon 20 NSCLC remains poor. Treatment with any chemotherapy regimen was most commonly used followed by EGFR TKIs in TN patients, while the proportion treated with chemotherapy and EGFR TKIs was similar in RR patients. Despite limited evidence in this population, over a fifth of TN and RR patients received EGFR TKI monotherapy. This study demonstrated unmet need for improved therapeutic options in TN and RR patients with NSCLC with EGFR exon 20 insertion mutation.

Cost Effectiveness of Avelumab for Metastatic Merkel Cell Carcinoma.

BackgroundMetastatic Merkel cell carcinoma (mMCC) is a rare and aggressive skin cancer. Until recently, there were no licensed treatment options for patients with mMCC, and prognosis was poor. A cost-effectiveness analysis was conducted for avelumab, a newly available treatment option for mMCC, versus standard care (SC), from a UK National Health Service perspective.MethodsA partitioned survival model was developed to assess the lifetime costs and effects of avelumab versus SC. Data from the JAVELIN Merkel 200 trial (NCT02155647) were used to inform estimates of quality-adjusted life-years (QALYs). Unit costs and associated frequencies of use were informed by published literature and clinical expert opinion. Results were presented as incremental cost-effectiveness ratios (ICERs, i.e. the cost per QALY gained) for treatment-experienced (TE) and treatment-naïve (TN) patients. Uncertainty was explored through a range of sensitivity analyses.ResultsDiscounting costs and QALYs at 3.5% per annum, avelumab was associated with ICERs of £35,274 (TE)/£39,178 (TN) per QALY gained. Probabilistic sensitivity analysis results demonstrated that avelumab was associated with an 88.3% (TE)/69.3% (TN) probability of being cost effective at a willingness-to-pay threshold for end-of-life treatments of £50,000 per QALY gained. Results were most sensitive to alternative survival extrapolations and dosing assumptions.ConclusionsThe analysis results suggest that avelumab is likely to be a cost-effective treatment option for UK mMCC patients. The results for TN patients are subject to some uncertainty, and a confirmatory analysis will be conducted with more mature data.

Phase 1 Study of the IDH1m Inhibitor FT-2102 As a Single Agent in Patients with IDH1m Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients and produce 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Herein, we present preclinical and clinical data from an ongoing Phase 1/2 study of single-agent (SA) FT-2102 in patients with IDH1m AML and MDS (CT.gov: NCT02719574).Methods: Extensive pre-clinical evaluations were performed on FT-2102, including CYP interactions in-vivo in rat and in-vitro in human tissue and in-vivo QTc toxicology in monkeys. The clinical Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion phases. FT-2102 was administered daily until disease progression or unacceptable toxicity. Eligibility criteria included: IDH1m AML/MDS [relapsed/refractory (R/R) or treatment naïve (TN) for whom standard therapy was contraindicated], adequate liver and renal function, no prior IDH1 inhibitors, and no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03.Results: Evaluation of FT-2102 in in-vivo rat and in-vitro human tissue indicated hepatic metabolism by CYP enzymes (CPY3A4, 2C9, 1A1) as the major route of excretion. Animal toxicology studies predicted the threshold for QTc risk occurred at exposures >5.5 fold higher than the murine exposure at which 90% 2-HG reduction was observed.In the clinical study, at the time of the data cutoff, 31 patients (pts) had been treated with SA FT-2102, with a median of 3 mo. on treatment (range: 0.2 to 20 mo.). Of the 31pts treated, 25 had AML (22 R/R; 3 TN) and 6 had MDS (4 R/R; 2 TN). The median number of prior anti-leukemia therapies was 2 (range: 0-9) for AML pts and 1 (range: 0-4) for MDS pts. FT-2102 doses were: 150 mg QD (n=8), 300 mg QD (n=4), 150 mg BID (n=16), and 100 mg QD with food (n=3). Eighteen pts discontinued treatment, most commonly due to death (n=5), progressive disease (n=5), HSCT (n=3), or lack of response (n=3).Severe (≥Grade 3) AEs occurring in >5% of pts included thrombocytopenia (26%), febrile neutropenia (23%), anemia (19%), pneumonia (13%), neutropenia (7%), hypokalemia (7%), pyrexia (7%) and leukocytosis (6%). Three pts had differentiation syndrome (IDH-DS), which resolved with temporary interruption of FT-2102, treatment with dexamethasone, hydroxyurea, and supportive care in all three. One pt had transient QTcF prolongation (Grade 3) which resolved with temporary interruption of FT-2102 and cessation of suspected concomitant medications. Eight pts died on treatment or within 28 days of the last dose, with no deaths considered related to FT-2102. No DLTs were observed during dose escalation.Selection of FT-2102 150 mg BID as the RP2D was supported by PK and PD data. Durable steady-state (Css) achieved by Week 2 was well below the threshold for QTc risk predicted by preclinical studies. The predicted IC90 was confirmed with prompt and durable 2-HG reduction to normal levels by C2D1 at the RP2D.Table 1 shows the Investigator-assessed ORR per IWG. Responses have been observed from 1 to 6 months on treatment, with stable disease observed beyond 6 months; 42% of the patients remain on treatment.Conclusions: FT-2102 preclinical evaluations suggest a low risk of clinically significant CYP-mediated drug-drug interaction and QTc prolongation. SA FT-2102 is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Significant clinical activity has been observed in heavily pre-treated and in TN patients, both in AML and MDS. FT-2102 continues being investigated at a dose of 150 mg BID in a Phase 2 study. Three SA Phase 2 cohorts are currently open for enrollment in R/R AML, AML/MDS with CR/CRi (i.e., with MRD), and in pts with R/R MDS/AML with prior exposure to an IDH1m inhibitor. Data updates will be available at the time of presentation. [Display omitted] DisclosuresLee:LAM Therapeutics: Research Funding; Karyopharm Therapeutics Inc: Consultancy; AstraZeneca: Consultancy; Clinipace: Consultancy; Amgen: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Ferrell:Incyte: Research Funding. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Role of Ibrutinib Based Regimen in Chronic Lymphocytic Leukemia

Background: Treatment of Chronic lymphocytic leukemia (CLL) depends on stage of disease, age, functional status, comorbidities and presence of cytogenetic abnormalities such as (del17p mutation). Ibrutinib was initially approved in CLL given its better response in del17p patients as compared to the standard chemo immunotherapy. Since initial approval, Ibrutinib has also been evaluated in del17p negative CLL patients. Aim of our study is to discuss the efficacy of ibrutinib based regimen in CLL.Methods: Seven databases (Pub Med/Medline, Elsevier/Embase, Elsevier/Scopus, Wiley/Cochrane Library, and Thomas Reuters/Web of Science, EBSCO/CINAHL, and ClinicalTrials.gov.) were searched in accordance with PRISMA statement guidelines using the following keywords: chronic lymphocytic leukemia, CLL, Bruton tyrosine kinase inhibitor, BTK inhibitor, ibrutinib, and PCI32765. Inclusion criteria included prospective clinical trials using Ibrutinib in CLL patients with outcome data available. We excluded systematic reviews, met analysis, case reports and case series. Aim of our review was to evaluate overall response rate (ORR), complete response rate (CR), progression free survival (PFS) and overall survival (OS).Results:Treatment naïve (TN)patientIn the extended 5-year median follow up of a phase 1/2b trial (n=31), the ORR with single agent Ibr was 87% (CR-29%). The 5-year PFS and OS was 92%. In phase 3 trial by Burger et al (2015), ORR with Ibr was 92% (CR18%) in 136 patients. 2-year PFS and OS was 89% and 95% respectively. Del17p patients were excluded. Recent phase 2 trial by Jain et al (2017), combination of ibr with fludarabine (flu), cyclophosphamide (cyclo) and obinutuzumab (G) achieved ORR of 100% (CR 46%) in 32 del17p negative patients. In the phase 2 trial by Davids et al (2017) in 49 patients (< 65 years) the ORR was 100% (CR 63%). Phase 1b/2 trial by Migouel, ORR was 96% (CR 52%) with a combination regimen of Ibr + G + venetoclax.Relapsed/refractory (R/R)patient:In a phase 3 trial by Byrd et al (2014), in 195 patients (median age: 67; del17p: 32%; median prior therapies: 3) the ORR was 63%(CR-O). Median follow up was 9.4 months with 6-month PFS of 88% and 12 months OS of 90%. Phase 2 trial by Burger et al (2014), the ORR was 95% (CR 8%) in 40 patients (median age:63%; del17p:50%; median prior therapies:2). The 18-month PFS and OS was 78% and 84% respectively. In the phase 3 trial by Chanan et al (2016), in 289 (median age 64) del17p negative patients with 2 median prior therapies treated with combination of Ibr + bendamustine + R, the ORR was 83% (CR 10%). The 18-month PFS was 79%. In the phase 3 trial by Sharman et al (2017), in the Ibr + ublituximab arm (n=64) the ORR was 78% (CR 7%) which was higher than in Ibr arm (n= 62) i.e 45% (CR 0). Median age was 67 and each arm received 3 median prior therapies. Del17p was positive in 64% and 66% respectively.Del17p patients: In the phase 2 trial of by Susan et al (2017), in 145 del17p positive patients (median age: 64) treated with Ibr, the ORR was 64% (CR 0). The median prior number of therapies was 2. Patients were followed for a median of 11.5 months and the 2-year PFS and OS was 63% and 75% respectively. Farooqui et al (2014) evaluated Ibr in del17p patients. In 35 TN patients the ORR was 97% (CR -0) with a 2 year PFS and OS of 82% and 84% respectively. In 16 R/R patients, ORR was 80% (CR 0) and the 2 year PFS and OS were 82% and 74% respectively. Median age was 62Conclusion: Ibrutinib is the treatment of choice for patients with del17p mutation and has good efficacy in RR/TN patients without del17p mutation. Ibrutinib is being evaluated in combination with rituximab for del17p mutations. Future prospects include combination of Ibrutinib with frontline chemotherapy and other novel agents for TN and RR del17p negative patients. DisclosuresNo relevant conflicts of interest to declare.

Ibrutinib, Single Agent BTK Inhibitor, for Treatment Naïve (TN) and Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia: A Real-Life Experience from Rete Ematologica Pugliese (REP)

Background: Ibrutinib is a first-in-class oral inhibitor of Bruton Tyrosine Kinase (BTK) approved for the treatment patients with CLL who have received at least one prior therapy (R/R) or Treatment Naïve (TN) with del17p. Ibrutinib has been showed to improve progression free survival (PFS) and overall survival (OS) even in presence of del17p. Moreover there is a good tolerability profile such as to not lead to frequent and permanent interruption of therapy.Methods: In 131 CLL/SLL patients (including previously treated and untreated with del17) from eight different hematologic centers of REP (Rete Ematologica Pugliese) Ibrutinib 420 mg once daily was administrated until disease progression or unacceptable toxicity. PFS, OS and Overall response rate (ORR) were calculated. Kaplan Meier method was used to estimate PFS/OS and differences in survival times between groups were assessed with a log-rank test.Results: Among 131 pts, 9 (6.9%) received Ibrutinib as first line therapy (TN) and 122 (R/R) received prior therapies before Ibrutinib (39.7% BR, 18.3% FCR and other treatments); 90% (1-2) lines of therapy, 8% (3-4) lines and 2% more than 5. Median age of the 131 pts with CLL/SLL was 65 y (range, 28-84) with 50% ≥65 y.ECOG Performance Status was observed in 108 pts (0, 56%; 1, 40%; 2, 4%). FISH analysis was performed in 85/131 pts (65%) and some patients had more than one deletion. Among these, 42% had del17p (TN 100% and R/R 36%) and for the remaining R/R was 16% del13q, 4% del11q, 7% trisomy12 and in the others no abnormalities were found. Unmutated and mutated IGVH was performed in 78/131 patients (60%), 63% and 37% respectively. The ORR was 80% (complete response [CR], 10%) for all-treated pts (TN: 86%, R/R: 77%) and for R/R pts with del17p the ORR was 61%.With a median time on study of 17 months (range, 1-45), median PFS was not reached for all TN or R/R patients and the estimated PFS at 30 months was 66,7% for R/R patients. We exclude from our further analysis 9 TN patients because of the small sample size and the lack of events in a median follow up of 15 months (range, 3-24). In 122 R/R pts, median PFS was 39 months for pts with del17p and median PFS was not reached for pts without abnormality (overall logrank p=0.543). At 30 m the estimated PFS was 65.1% for del17p pts and 80.4% for no abnormality pts . Median OS was not reached for 122 R/R patients and the estimated PFS at 30 months was 72.7%. Median OS was not reached in pts with and without del17p (overall logrank p=0.807) with an estimated OS at 30 months of 81.7% and 90.2% respectively.In 47% of all treated patients adverse events (AEs) with grade ≥3 were neutropenia (16%), hypertension (12%), atrial fibrillation (3%), anemia (3%), diarrhea (2%). With a median follow up of 17 months 80% of pts remain on Ibrutinib treatment.Conclusions: In our real life experience with data from REP, Ibrutinib single agent demonstred to be effective. In R/R patients, with a median time on study of 17 months, the estimated PFS at 30 m was 66.7%. The differences in PFS between patients with and without del17p was not statistically significant (p=0.543) but at 30 months the estimated PFS was lower in del17p pts than in no abnormality pts (65.1% vs 80.4%).The treatment was well tolerated with AEs of grade ≥3 in a low percentage (36%) that did not result in treatment interruptions in the most of cases. Clearly, these results will require longer follow up time to be further confirmed. DisclosuresNo relevant conflicts of interest to declare.