Unmutated IGHV Status Research Articles

Gender, Age and TP53 Aberrations in Context of Complex Karyotypes in Chronic Lymphocytic Leukemia Patients in the Era of Chemo +/- Immunotherapy

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia characterized by a heterogeneous course of the disease. Determination of prognosis of patients (pts) is based on clinical and laboratory parameters, where cytogenetic examination plays a significant role. According to recent studies the complex karyotype (CK) shows to have adverse prognostic value and occurrence of CK is reported in 15-20% of untreated pts. Multiple diverse chromosomal translocations, deletions, duplications, numerical changes or dicentric chromosomes arise within complex karyotypes.Our aims were to determine the CK frequency in our cohort of untreated CLL pts, to verify its prognostic significance and to validate whether TP53 disruptions or ATM deletions involved in CK affect survival of pts. Moreover we aimed to investigate types of chromosomal aberrations implied within the CK in detail and to identify their possible adverse prognostic impact.A total of 644 untreated CLL pts (diagnosed according to iwCLL criteria) were examined at Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic (in years 1996-2017). Peripheral blood or bone marrow samples were examined by classical and molecular cytogenetic and molecular genetic methods (G-banding, FISH, mFISH, arrayCGH, PCR, sequencing, NGS - Illumina, MiSeq) using standard protocols.CK was detected in 79 pts (12.3%, 57 men and 22 women), median of age at diagnosis was 64 years (34-87 years). The most frequently detected recurrent changes in pts with CK were deletions of 13q14 (68%), 11q22 (43%), 17p13 (33%) and duplication of 8q24 (27%). Chromosomes mostly included in CK were chromosomes 13, 11, 17, 2, 8 and 6, respectively. Sixty pts (76%) had unmutated IGHV status and 6 pts (8%) mutated IGHV3-21 . TP53 gene mutations were detected in 25 pts out of 71 examined ptswith CK (35%), 19 of pts (27%) had both deletion and TP53 mutation.Statistical analysis has shown a lower overall survival (OS) rate of CK pts compared to pts without CK (77 months vs. 115 months, p<0.0001). We also observed influence of gender and age on the OS of CK pts. More adverse outcome has been seen in women with CK compared to women without CK (37 months vs. 154 months, p<0.0001; men with CK vs. men without CK 84 months vs. 106 months, p = 0.0049) and also in pts with CK with age over 60 years (pts with CK over 60 vs. pts with CK under 60: 68 months vs. 123 months, p=0.0075). The effect of presence of translocations, numerical changes and dicentric chromosomes as part of the CK on patient´s survival has not been demonstrated (p=0.5; p=0.35; p=0.62). The deletions of TP53 and ATM genes have not occurred simultaneously in our CK cohort and the survival of these pts has not been worse. Nevertheless we could see a trend to worse survival in pts with CK and TP53 deletion/mutation (p=0.076). However, pts without CK with the occurrence of ATM or TP5 3 deletions have had a comparable negative prognostic impact just as the pts with CK (p=0.37/p=0.78).In accordance with other authors we proved that pts with CK occurring before treatment had significantly shorter survival compared to pts without CK. Importantly, the occurrence of CK in CLL has the worst impact on OS of pts older than 60 years. Moreover OS has shortened the most significantly in women with CK compared to women without CK in our single center experience. To our best knowledge these findings was not reported by other authors so far. To explain this phenomenon it would be necessary to extend studied cohort of pts with CK. Using of standard cytogenetic methods completed with modern molecular genetic analyses remains essential for risk stratification of CLL pts. Finally, not only pts with TP53 aberrations, but also pts with CK could be possible candidates for new treatment approaches.This work was supported by grants: VES16-32339A, IGA_LF_2017_007. DisclosuresPapajik:Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Research Funding; Roche: Other: Travel/accomodation expenses, Speakers Bureau.

Improving Depth of Response with Continued Ibrutinib Therapy in CLL Patients

Introduction: Minimal residual disease negativity (MRD-) predicts long-term survival of CLL patients after chemoimmunotherapy. Data on depth of response and its clinical significance in patients receiving ibrutinib is limited. The fact that ibrutinib is a time-indefinite therapy, as opposed to the time-limited approach with classic chemoimmunotherapy, raises the question of temporal MRD changes during continued treatment. We sequentially quantified MRD in peripheral blood (PB) and bone marrow (BM) by flow cytometry in CLL patients on ibrutinib.Methods and Patients: 86 CLL patients received single-agent ibrutinib 420mg once daily under a phase II investigator-initiated trial (NCT01500733). 3-year safety and efficacy results from this trial were previously reported [Farooqui et al, 2015 ASH Abstract 2937]. Briefly, eligible patients had either TP53 aberration or were ≥65 years old. The study included both treatment-naïve and relapsed/refractory patients. The primary endpoint was response at 6 months according to 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria incorporating 2012 clarifications. Response assessments at 6 and 12 months and annually thereafter included PB and BM flow cytometry and BM biopsy. MRD- was defined as <10-4 CLL cells per leukocytes based on 8-color flow cytometry. Spearman's analysis was used to assess the correlation between PB and BM MRD. Linear mixed models for repeated measures were used to estimate annual reduction of disease burden. Statistical analyses were performed using R (version 3.4.0).Result: Of 86 patients enrolled, 51 (59.3%) patients had TP53 aberration and 35 (40.7%) patients were ≥65 years old. More than half of the patients had previously untreated CLL (53 [62.6%]), advanced Rai stage (58 [67.4%]), and unmutated IGHV (U- IGHV) status (57 [66.3%]). At the median follow-up of 48 months, 52 (60.5%) remained on study. CLL disease burden significantly and continuously decreased with therapy in both PB and BM. Comparison of the paired PB and BM MRD levels revealed strong correlation between the two compartments (P <0.0001). Past the first year, residual CLL burden decreased by 36% in PB and 28% in BM with each additional year of treatment. Median MRD at 3 years was 5.3x10-2 in PB and 7.3x10-2 in BM. Although depth of response significantly improved over time, MRD- (<10-4) was rare even with long-term therapy. Three patients achieved MRD- in PB (each at 2, 3 and 4 years) and three patients achieved MRD- in BM (two at 3 years and one at 4 years, respectively). Low MRD (<10-2) was achieved by 16 (25.4%) of 63 patients at 3 years. We correlated MRD levels to iwCLL response. The CR rate of 38% in the low MRD group was not significantly different from 23% in the high MRD group (P=0.33). Likewise, both MRD groups showed comparable levels of residual disease in lymph nodes, spleen, and BM. Next, we performed subgroup analyses using baseline characteristics to identify factors associated with differential levels of MRD. MRD levels were similar between subgroups stratified by TP53 aberration and prior treatment status. Notably, patients with U- IGHV had significantly lower MRD in PB than patients with mutated IGHV (M- IGHV) starting from the first year on ibrutinib (P <0.05; Figure 1). However, BM MRD levels were similar between IGHV subgroups.Conclusion: Depth of response improved with continued ibrutinib, leading to low levels of MRD. PB and BM MRD levels were highly correlated, suggesting non-invasive testing could replace BM assessments on ibrutinib. Patients with M- IGHV had significantly higher levels of PB MRD than those with U- IGHV, consistent with known differences in redistribution lymphocytosis between two subgroups. Studies using MRD as a decision point for treatment duration with ibrutinib need to take into consideration the different levels of PB MRD achieved in the two IGHV subgroups. [Display omitted] DisclosuresWiestner:Pharmacyclics: Research Funding; Acerta Pharma: Research Funding.

BCR-Assosiated Kinase Inhibition in Relapsed/Refractory Chronic Lymphocytic Leukemia. Real World Experiences of a German Regional Clinical Register

Background: The advent of B-cell-receptor associated kinase inhibition (BCR-KI) inaugurated a novel therapeutic principle in chronic lymphocytic leukemia (CLL). First-in-class Ibrutinib (Ib) and Idelalisib (Id) received marketing authorization from the EMA for the treatment of relapsed/refractory (r/r) CLL in 2012 and 2014, respectively. In spite of ample evidence from trials, real life data are scarce. Methods: Our clinical registry has been previously described in detail [https://doi.org/10.1182/blood-2018-99-110618]. It comprises of 168 unselected CLL patients (pts.), who were observed between 10/2014 and 08/2020. 65 of them required treatment during this period: 39 x 1st line only and 26 x &amp;gt; 2nd line. 18 of these 26 r/r CLL pts were treated either with Ib (11 x) or Id (7 x). Treatment was started according to iwCLL guidelines. The type of BCR-KI was chosen based on an individual's performance status, previous treatment and co-morbidity. Median 1st line-treatment (as a rule immunochemotherapy) started 27.5 months (m) after diagnosis (range: 0.5 m to 87.5 m). Time from 1st line therapy to BCR-KI treatment ('Ctx effected time') was 13.0 to 128.1 m (median 50.5 m), in total (18 pts.) 1052.5 m, i.e. 87.7 years (y). 17 of 18 pts. had received Rituximab (R) as part of a pre-BCR-treatment protocol. Estimated charges per month are 9.000 € in Id + R, 7.000 € in R + chemotherapy (ctx, i.e. Fludara or Bendamustin mostly) and 4.500 € in Ib or Id mono or R + Chlorambucil (Clb) respectively. Results: Patients described herein differed according to age at start of BCR-KI (44.4 to 86.8 y, median 76.0 y), sex (10 m, 8 f), types and lines (1 to 6, median 2) of prior treatment. Indications for BCR-KI were increasing tumor burden (17 x, 1 x combined with pleural effusion) and persistent hemolysis (1 x). Genetic high risk features comprised of at least one of the following: IGHV unmutated status, mutation and/or deletion of TP53 gene, deletion of 11q, and complexe karyotype. These features were present in 17 of 18 pts. (median 3 features). In particular, unmutated IGHV was found in 13/18 r/r pts who received BCR-KI (total cohort of r/r pts, 21/26). Overall response rate was 78% (Ib 8/11; Id 6/7). Time to next therapy or death (`KI effected time`) varies from 1.1 m to 69.1 m - in total 286.9 m until now. 4 pts. continued BCR-KI from 30 to 67 months. This was always the longest period of unchanged therapy in these 4 pts. Shorter `KI effected time` in the other 14 pts. was associated with higher treatment line and treatment interruptions. 2 responding pts. (without side effects) stopped BCR-KI and stayed in ongoing hematological remission for 11 and 25 months after cessation of treatment. Adverse drug reactions occurred in 6 pts. (Ib 4 x, Id 2 x). 5 pts. died on BCR-KI, but there was no therapy related death. Approximate costs per month in Germany are 1700 € in `Ctx effected time` (1.800.000 € per 1052,9 m) and 4.700 € in `KI effected time` (1.350.000 € per 286,9 m). Of note, one pt. on Id showed clinical progression associated with genetic evolution after 67 months of BCR-KI. He promptly responded to venetoclax. Discussion: In real live many r/r CLL pts. are elderly and present a broad spectrum of different clinical features. A clinical registry can reflect this and may add to our knowledge from multicenter studies. Remarkably almost all of our unselected r/r CLL pts. revealed genetic high risk features, in particular unmutated IGHV status, making them ideal candidates for targeted treatment strategies. These strategies take advantage of the fact that BCR-KI has been demonstrated to be well tolerated and effective in elderly and pre-treated pts. Undoubtedly BCR-KI increases the total costs of therapy, but affords a prolongation of overall survival. Remaining open questions include optimal treatment sequences, combination partners for BCR-KI as well as thorough analysis in the quality of molecular remissions. Disclosures Böttcher: Janssen: Honoraria, Research Funding; Celgene: Research Funding; AbbVie: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Honoraria.

Robust Discovery of Candidate DNA Methylation Cancer Drivers

Robust Discovery of Candidate DNA Methylation Cancer Drivers

Bendamustine Followed By Obinutuzumab and Idelalisib in Patients with Chronic Lymphocytic Leukemia (CLL): CLL2-BCG Trial of the German CLL Study Group (GCLLSG)

Bendamustine Followed By Obinutuzumab and Idelalisib in Patients with Chronic Lymphocytic Leukemia (CLL): CLL2-BCG Trial of the German CLL Study Group (GCLLSG)

Clinico-Biological, Molecular and Prognostic Features of Patients with Diffuse Large B-Cell Lymphoma-Variant of Richter Syndrome: A Multicenter Retrospective Study of the French Innovative Leukemia Organization

Clinico-Biological, Molecular and Prognostic Features of Patients with Diffuse Large B-Cell Lymphoma-Variant of Richter Syndrome: A Multicenter Retrospective Study of the French Innovative Leukemia Organization

Blinatumomab after R-CHOP Debulking Therapy for Patients with Richter Transformation: Preliminary Results of the Multicenter Phase 2 Blinart Trial from the Filo Group

Background Richter syndrome (RS) refers as to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients (pts) with chronic lymphocytic leukemia (CLL). The outcome of RS pts is usually very poor with both low response rates to chemoimmunotherapy and short survival, except for the minority of them whose tumor cells are clonally unrelated to the underlying CLL. While BCR and BCL2 inhibitors have transformed the management of CLL pts, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017). Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of pts with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. More recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in pts with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016). We hypothesized that blinatumomab would improve response in RS pts failing to achieve CR after initial debulking with R-CHOP. Methods We report here the first results of a currently ongoing phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for pts with untreated RS of DLBCL histology (NCT03931642). The pts achieving complete remission (CR) after 2 cycles of R-CHOP21 discontinued study while those with persisting (PR, SD) or progressive disease (PD) were eligible to receive an 8-week course of blinatumomab induction. An additional 4-week consolidation cycle was optional and might be proposed according to the treating-physician decision, especially in pts who were ineligible for stem-cell transplantation. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. Interim analysis (Simon two-stage design) was planned after completion of blinatumomab induction in 10 pts. Results A total of 15 pts out of 35 has already been enrolled in the trial to date. Median age was 67 years (range, 38-80) andsex ratioM/F was 12/3. CLL features at baseline were as follows: 9/15 (60%) pts hadTP53alterations and 10/13 (77%) unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-4): 10 (67%) pts previously received chemo-immunotherapy, 10 (67%) pts were exposed to BCR inhibitors and 3 (20%) to venetoclax. As of the data cut-off of July 1st, 2020, the blinatumomab induction course has been completed for 5 pts while it is still on-going in 3 others. Three pts are still on R-CHOP debulking. Four pts discontinued study before receiving blinatumomab for the following reasons: 2 pts achieved CR after R-CHOP, 1 patient died because of febrile neutropenia after R-CHOP and 1 patient discontinued study before starting R-CHOP (no RS criteria after pathology review). Regarding toxicity during blinatumomab, data are available for the 5 pts having completed the blinatumomab induction to date. Four pts had at least one grade 1 adverse event (AE), 2 had grade ≥3 AE. The most common AE, regardless of relationship to blinatumomab, were grade 1 fever (2 pts) and grade 2 leukopenia (2 pts). Other grade &amp;gt;1 AE were observed in 1 pt only (grade 3 anxiety, grade 2 anemia, grade 2 neutropenia, grade 3 lymphopenia). In terms of neurologic event, 1 pt had grade 1 AE (paresthesia, myoclonus and muscle contraction) and another one presented grade 4 confusion while on first 9 μg/d dose leading to permanent discontinuation of blinatumomab. In terms of efficacy, after R-CHOP debulking therapy (n=10 evaluable pts), 2 pts achieved CR (and did not pursuit on study), 5 pts were in PR and 3 pts were progressive. At evaluation after the blinatumomab induction (n=5 evaluable pts), 2 pts achieved CR, 1 patient PR and 2 pts were progressive. Conclusions Our preliminary data suggest that blinatumomab shows encouraging anti-tumor activity and acceptable toxicity in pts with RS. Further analyses are warranted to validate these conclusions. Updated efficacy/safety in the remaining pts enrolled in the trial will be presented at the meeting. Disclosures Guieze: astrazanecka:Honoraria, Other: advisory board;gilead:Honoraria, Other: travel funds;janssen cilag:Honoraria, Other: advisory board, travel funds;roche:Other: travle funds;abbvie:Honoraria, Other: advisory board, travel funds.Ysebaert:AbbVie:Consultancy;Janssen:Consultancy;Roche:Consultancy.Fornecker:Roche:Consultancy;Takeda:Consultancy.Broséus:Gilead:Honoraria;AstraZeneca:Consultancy, Honoraria;Janssen:Honoraria, Research Funding;Novartis:Honoraria, Research Funding.Feugier:astrazeneca:Consultancy, Honoraria, Research Funding;abbvie:Consultancy, Honoraria, Research Funding;roche:Consultancy, Honoraria, Research Funding;gilead:Consultancy, Honoraria, Research Funding;janssen:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells. It has been approved as a second line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia.

Comparison of Clinical and Laboratory Features, Drug Availability, and Outcomes of CLL Patients Treated in Public or in Private Hospitals in Brazil: A Retrospective Analysis of the Brazilian Registry of CLL

Introduction: Chronic lymphocytic leukemia (CLL) typically occurs in elderly patients and has a highly variable clinical course. It is important to understand the aspects that affect the outcomes of CLL in a real-world setting. Besides biological factors, other socioeconomic and health system factors may influence the clinical course of CLL. Hence, data from the Brazilian Registry of CLL was analyzed to compare clinical and treatment-related characteristics in patients with CLL treated in public or in private institutions in Brazil. Objective: To describe the outcomes of a series of CLL patients followed in public or in private hospitals in Brazil. Methods: The Brazilian Registry of CLL was started in 2004 as a prospective non-interventional data collection tool. Inclusion criteria for enrollment followed the IWCLL guidelines. For this analysis, we included all patients with minimum available data for analysis of patient and disease characteristics and survival. Results/discussion: From January 2004 to July 2020, 2927 patients from 37 centers met eligibility criteria for this analysis: 2324 (79%) were followed at public hospitals and 603 (21%) at private hospitals. The majority were male (57%), with median age of 65 years (ranging from 23 to 106). Binet stage was A in 1618 (58%) patients, B in 628 (23%) and C in 525 (19%). FISH for del(17p) was performed in only 479 patients (16%), while FISH for the most common aberrations [del(13q), +12, del(11q), and del(17p)] was performed in only 445 patients (15%). IGVH mutational status was performed in only 211 patients (7%), and karyotype in only 140 patients (5%). Comparing public and private hospitals, we observed that patients in public hospital are slightly older (median age 66 years vs. 64 years for private hospitals, P=0.04), had more advanced diseases at diagnosis (frequency of Binet B or C was 44% in public vs. 32% in private hospital, P&amp;lt;0.0001), and there were more patients with elevated creatinine levels (14% vs. 10%, P=0.03). All prognostic markers were significantly more available in private than in public hospitals: FISH for del17p (42% of cases vs. 10%, respectively, P&amp;lt;0.0001), IGVH mutational status (13% vs. 6%, respectively, P&amp;lt;0.0001) and karyotype (16% vs. 2%, respectively, P&amp;lt;0.0001). The frequency of del(17p) was similar between public and private hospitals (10% vs. 11%, P=NS), while the frequency of unmutated IGHV status was more common in private hospitals, although not statistically different (60% vs. 48%, P=0.09). Analyzing 2102 diagnosed after 2010, we observed that 864 patients (41%) were treated after a median time of 7 months (range: 0-267) after diagnosis. First line treatment was predominantly based chlorambucil (45%) or fludarabine (40%). Anti-CD20 monoclonal antibody was used in only 39% of cases: (rituximab in 35% and obinutuzumab in 4%). Novel agents were used in first line in only 2% of patients, and in most cases in the context of a clinical trial. Of note, most patients (86%) with del(17p) detected by FISH were treated with chemoimmunotherapy. When comparing treatments between public or private hospitals we observed striking differences: in public hospitals there were significantly less patients receiving fludarabine-base regimens (36% vs. 54%, P&amp;lt;0.0001), and anti-CD20 monoclonal antibodies (28% vs. 78%, P&amp;lt;0.0001). Overall survival at 6 years was significantly worse in public than in private hospitals (72% vs. 93%, respectively, P&amp;lt;0.0001). After a multivariate analysis, survival in patients from public hospitals remained significantly worse than in private hospitals (hazard ratio 3.4, 95% confidence interval 2.4 - 4.8), after correcting for age, Binet staging and renal function. Conclusion: Our data indicate that are striking differences between patients treated in public or private hospitals in Brazil. The lack of accessibility to basic laboratory tests for prognostic factors and adequate therapies probably explains the worse outcome of patients treated in public institutions. In fact, prognostic testing rates were poor in both contexts and most high-risk patients received chemoimmunotherapy first-line. Urgent strategies are needed to increase accessibility to prognostic testing and to novel agents for quality improvement in health care in CLL patients in Brazil. Disclosures No relevant conflicts of interest to declare.

Comparison Between Venetoclax-based and Bruton Tyrosine Kinase Inhibitor-based Therapy as Upfront Treatment of Chronic Lymphocytic Leukemia (CLL): A Systematic Review and Network Meta-analysis

BackgroundAvailable targeted agents (TAs) for the upfront therapy of chronic lymphocytic leukemia (ie, ibrutinib, acalabrutinib, venetoclax) have rarely been compared in head-to-head clinical trials. In search of data for evidence-based treatment decisions, a systematic literature review and network meta-analysis was performed. Materials and MethodsThe screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA). ResultsOnly 3 trials were suitable for the base-case network analysis (ILLUMINATE, ELEVATE-TN, and CLL14). Regarding progression-free survival (PFS), fixed-effect analyses comparing ibrutinib-obinutuzumab (IO) with venetoclax-obinutuzumab (VO) (relative risk [RR], 1.52; 95% confidence interval [CI], 0.82-2.81), acalabrutinib (A) with IO (RR, 0.87; 95% CI, 0.47-1.61), and A with VO (RR, 0.57; 95% CI, 0.32-1.01) revealed that the upper limit of the 95% CI for RR did exceed the 1.0 value. This indicates a lack of significant difference in PFS for IO, VO, and A. In contrast, acalabrutinib plus obinutuzumab (AO) improved PFS in comparison with IO (RR, 0.43; 95% CI, 0.22-0.87) and VO (RR, 0.29; 95% CI, 0.15-0.56). No differences in the frequency of adverse events was observed across different TAs. Also, the analysis of PFS in relationship with high-risk genetic features (ie, TP53 aberrations, IGHV unmutated, 11q deletion) showed similar results for different TAs. However, patients with unmutated IGHV status fared better with AO than with VO in terms of PFS. ConclusionsThis systematic review and network meta-analysis indicated that upfront AO prolongs PFS in comparison with IO and VO, whereas no differences are observed between IO, VO, and single-agent A. Hopefully, ongoing studies will further delineate the position of different TAs in chronic lymphocytic leukemia therapy based on effectiveness, availability, safety, cost, and treatment objectives.

CLL-251: Venetoclax for CLL Patients Outside Clinical Trials: An Italian Real-Life Experience

Context CLL is living a chemo-free era thanks to B-Cell Receptor inhibitors (BCRi), such as ibrutinib and idelalisib, and the BCL2-inhibitor venetoclax. In patients that experienced progression or side effects with BCRi, scientific literature indicates that venetoclax may provide a good alternative. In Italy, venetoclax monotherapy in R/R CLL patients was approved from August 2017; while in association with immunotherapy was not available until December 2019. Objective Our goal was to evaluate safety and efficacy of venetoclax in a real-life setting. Design Using an extraction sheet, we collected biological and clinical data from patients treated with venetoclax from October 2017 to April 2020. Patients Overall, 38 patients received venetoclax: median age was 66 years, 65% had high-risk disease (17p-/TP53 disruption/11q-), 84% had unmutated IGHV status. 35% were unfit (CIRS > 6). 68% had been treated with more than two therapy lines before venetoclax: 8 were BCRi-naive, 25 received single BCRi before venetoclax (18 ibrutinib, 7 idelalisib), and 5 patients received both BCRi. One patient was re-treated with venetoclax monotherapy after MURANO. Interventions Every patient has received venetoclax for at least 5 months. Main outcome measures Overall-response rate (ORR) and safety were primary endpoints. Secondary endpoints were progression-free survival (PFS) and overall-survival (OS). Results During the Ramp-Up phase, no TLS was registered. With a median follow-up of 20 months, cumulative ORR was 75% (CR 25%). No differences were observed, in terms of ORR, between patients with high-risk disease and normal risk (p:0.78).12-months PFS and OS were 62% and 63%, respectively. Hematological toxicity occurred in 5 patients, requiring a dose reduction. No patients experienced extra-hematological toxicity. PD was observed in 3 patients, 2 of them developed Richter Syndrome. Median discontinuation time was 8 months. Of 29 patients alive, 23 are still receiving venetoclax for a median time of 18 months. Conclusions We observed a good response and tolerance in our heavily pre-treated and elderly patients. Accordance with literature, venetoclax achieves best results when it is administered after single BCRi. Our preliminary results are comparable with published data, confirming the safety of venetoclax in this subset of patients.

CLL-384: Proliferation and Unmutated IGHV Status are Associated with Homologous Recombination Activity in CLL Cells

In IgHV-unmutated CLL (U-CLL), the proliferation rate is higher compared with IGHV-mutated CLL (M-CLL). Yet, why CLL cells differ in their mutational rates is unknown. Accumulating mutations in the IGHV gene lead to subsequent accumulation of DNA breaks. In rapidly dividing cells, DNA breaks are repaired by the efficient high-fidelity homology-directed DNA (HR) repair apparatus, whereas in slowly dividing cells, they are repaired by the inefficient low-fidelity nonhomologous end-joining (NHEJ) repair mechanism. Since HR is a high-fidelity DNA repair process, we expect that in cells that preferentially utilize HR, the mutations will be substituted by non-mutated (“germline”) nucleotides. We therefore postulate that proliferating U-CLLs utilize HR, which corrects the mutations accumulated during SHM. To test whether U-CLL cells preferentially use HR, we incubated CLL cells from two patients with U-CLL and two patients with M-CLL with antibodies that bind RPA and RAD51, key components in the HR repair pathway. By fluorescence microscopy, we detected these proteins in U-CLL, but not M-CLL, cells. To confirm these findings, we quantified the transcript levels of key players in the DNA repair process by qRT-PCR in four patients with M-CLL and two patients with U-CLL. Consistent with the immunohistochemistry data, the levels of FANCD2, RAD51, BRCA1 and BRCA2, which represent HR, were significantly higher in U-CLL compared with M-CLL. Levels of XRCC5, XRCC6, and PRKDC, which represent the NHEJ machinery, were low across all samples tested. Since HR is only operative in dividing cells, we hypothesized that inducing proliferation will turn on the HR enzymatic machinery. To induce proliferation, we incubated CLL cells from eight patients with CpG oligonucleotide. Using this agonist, proliferation increased by 110% (range: 42 to 250) in M-CLL cells but only by 25% (range 14 to 66) in U-CLL cells. The increase in proliferation rates correlated with upregulation of the HR machinery at the RNA and protein levels as measured by qRT-PCR and immunohistochemistry, respectively. Summary Here, we show that proliferating CLL cells utilize more often HR recombination repair machinery. Whether HR activity contributes to reduced mutational rates in the IGHV gene remains to be determined.

AMG-176, an Mcl-1 Antagonist, Shows Preclinical Efficacy in Chronic Lymphocytic Leukemia.

Survival of CLL cells due to the presence of Bcl-2 and Mcl-1 has been established. Direct inhibition of Bcl-2 by venetoclax and indirect targeting of Mcl-1 with transcription inhibitors have been successful approaches for CLL. AMG-176 is a selective and direct antagonist of Mcl-1, which has shown efficacy in several hematologic malignancies; however, its effect on CLL is elusive. We evaluated biological and molecular effects of AMG-176 in primary CLL cells. Using samples from patients (n = 74) with CLL, we tested effects of AMG-176 on CLL and normal hematopoietic cell death and compared importance of CLL prognostic factors on this biological activity. We evaluated CLL cell apoptosis in the presence of stromal cells and identified cell death pathway including stabilization of Mcl-1 protein. Finally, we tested a couplet of AMG-176 and venetoclax in CLL lymphocytes. AMG-176 incubations resulted in time- and dose-dependent CLL cell death. At 100 and 300 nmol/L, there was 30% and 45% cell death at 24 hours. These concentrations did not result in significant cell death in normal hematopoietic cells. Presence of stroma did not affect AMG-176-induced CLL cell death. IGHV unmutated status, high β2M and Mcl-1 protein levels resulted in slightly lower cell death. Mcl-1, but not Bcl-2 protein levels, in CLL cells increased with AMG-176. Low concentrations of venetoclax (1-30 nmol/L) were additive or synergistic with AMG-176. AMG-176 is active in inducing CLL cell death while sparing normal blood cells. Combination with low-dose venetoclax was additive or synergistic.

Fixed-duration venetoclax-obinutuzumab for previously untreated patients with chronic lymphocytic leukemia: Follow-up of efficacy and safety results from the multicenter, open-label, randomized, phase III CLL14 trial.

8027 Background: The CLL14 trial demonstrated significant improvement of progression-free survival (PFS) with fixed-duration venetoclax-obinutuzumab (VenG) as compared to chlorambucil-obinutuzumab (ClbG) in patients with previously untreated CLL and coexisting conditions. Here, we report follow-up data on safety and efficacy. Methods: Patients with previously untreated CLL and coexisting conditions were randomized 1:1 to receive 12 cycles of venetoclax with 6 cycles of obinutuzumab or 12 cycles of chlorambucil with 6 cycles of obinutuzumab. Primary endpoint was investigator-assessed progression-free survival. Key secondary endpoints were response rates, rates of minimal residual disease (measured every 6 months up to 5 years after last patient enrolment) and overall survival. Follow-up is ongoing but all patients are off study treatment. This trial was registered with ClinicalTrials.gov, number NCT02242942. Results: Of the 432 enrolled patients, 216 were randomly assigned to receive VenG and 216 to receive ClbG. After a median follow-up of 39.6 months (interquartile range 36.75 - 43.04), progression-free survival continued to be superior for VenG as compared to ClbG (median not reached vs 35.6 months; hazard ratio [HR] 0.31 [0.22-0.44], p &lt; 0.001). At 3 years, the estimated progression-free survival rate was 81.9% in the VenG arm and 49.5% in the ClbG arm. This benefit was consistently observed across all clinical and biological risk groups, including patients with TP53 mutation/deletion and unmutated IGHV status. Of note, PFS was also significantly longer for VenG treated patients with mutated IGHV status. Assessment of minimal residual disease 18 months after end of treatment showed that 47.2% of patients in the VenG arm had undetectable (u) uMRD ( &lt; 10−4), 13% had low (L)-MRD (≥ 10−4 and &lt; 10−2) and 7.9% high (H)-MRD (≥ 10−2), compared to 7.4% uMRD, 17.1% L-MRD, 26.9% H-MRD in the ClbG arm. No difference has been observed (HR 1.027, 95% CI 0.602-1.753, p = 0.921) for overall survival; median overall survival has not been reached in either group. Second primary malignancies were reported in 36 (17%) patients in the VenG arm and 22 (10.3%) in the ClbG arm. No new safety signals were observed. Conclusions: The results suggest that the superior efficacy and deep remissions after fixed-duration VenG are maintained during extended follow-up, and show the long-term benefits of 12 cycles of VenG across all known risk categories. Clinical trial information: NCT02242942 .

Mantle Cell Lymphoma: History, Current Principles of Diagnosis, and Treatment (Literature Review)

Mantle cell lymphoma (MCL) is a heterogeneous disease with a broad spectrum of clinical manifestations from rare indolent cases requiring no immediate treatment to aggressive fast-proliferating tumors. Differences in clinical behavior are rooted in molecular grounds which in the latest edition of WHO hematopoietic and lymphoid tissue tumor classification formed the basis for dividing MCL into two variants: classical (in most cases) and indolent. In last decades, our insight into biology and disease development mechanisms has been considerably enhanced. Further, it will help to risk stratify patients not only according to clinical factors (MIPI) but also taking into account molecular and biological properties of tumor (Ki-67 proliferation index, ТР53, NOTCH1, and NOTCH2 mutations, complex karyotype, and unmutated IGHV status). Treatment algorithms based on intensive chemotherapy with high-dose cytarabine and autologous hematopoietic stem cell transplantation with further rituxi-mab maintenance therapy ensure long-term monitoring of the disease in many MCL patients. The use of new “chemo-free” regimens and rational combinations (bortezomib, BTK inhibitors, lenalidomide, and venetoclax) offers the hope of a departure from conventional chemotherapy for a certain part of patients. Novel drugs with unique modes of action enabled, to some extent, to deconstruct the stigma of MCL fatality.

Treatment strategies for chronic lymphocytic leukemia in the era of novel targeted therapies

Molecular targeted therapies with small molecule inhibitors and antibodies have rapidly replaced chemoimmunotherapy, which has been the gold standard of care for patients with chronic lymphocytic leukemia (CLL). We discuss the current treatment strategies for CLL with special emphasis on genomic and molecular risk factors including IGHV unmutated status, 11q deletion, and 17p deletion. Ibrutinib and venetoclax are two molecular targeted agents currently available in Japan. They are highly effective, well tolerated, and have improved overall survival. Therefore, molecular targeted therapies are preferred to chemoimmunotherapy for most patients. Ongoing studies will clarify the optimal option between combination and sequence of treatment regimens with an appropriate timing of therapeutic intervention for longer survival. We are nearing an era of chemotherapy-free CLL management.

Bendamustine, Followed by Ofatumumab and Ibrutinib in Chronic Lymphocytic Leukaemia (CLL2-BIO): Primary Endpoint Analysis of a Multicentre, Open-Label Phase-II Trial

Background: The introduction of targeted agents has revolutionized the treatment of CLL but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. Methods: This multicentre, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumour load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Findings: Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease (MRD) negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias and anaemia during the debulking with bendamustine and neutropenias, infusion-related reactions and diarrhoea during the induction with ofatumumab and ibrutinib. Interpretation: This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an overall response rate of 92%. Ongoing maintenance treatment aims at deeper responses with MRD negativity. Clinical Trial Registration: (clinicaltrials.gov number: NCT02689141) Funding Statement: Novartis, GlaxoSmithKline and Janssen. Declaration of Interests: PC reports research funding from AbbVie, Acerta, F. Hoffmann-LaRoche, Gilead, GlaxoSmithKline, Janssen-Cilag and Novartis, honoraria for scientific talks by AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag and for advisory boards by AbbVie, Acerta, AstraZeneca, Janssen-Cilag and Novartis, as well as travel grants by AbbVie, F. Hoffmann LaRoche, Gilead, Janssen-Cilag and Mundipharma. JvT reports research funding from F. Hoffmann-LaRoche and Janssen-Cilag, honoraria for advisory boards by AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag, as well as travel grants by Celgene, F. Hoffmann-LaRoche and Janssen-Cilag. JB reports honoraria and travel grants by F. Hoffmann-LaRoche. PL reports research funding from AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag, honoraria Janssen-Cilag and travel grants from F. Hoffmann-LaRoche, Janssen-Cilag and Mundipharma. OA-S reports personal fees from F. Hoffmann-LaRoche, AbbVie and Gilead. WH reports research funding by MSD (Merck Shap & Dohme) and Pfizer, honoraria for scientific talks by Alexion, Basilea, Gilead, MSD (Merck Shap & Dohme) and Pfizer, advisory boards by Gilead Science, MSD, Pfizer, travel grants by Alexion, Astellas, Basilea, Gilead Science, MSD and Pfizer (all outside the submitted work). UVK reports honoraria for advisory boards by AbbVie, Amgen, F. Hoffmann-LaRoche, Gilead, Lilly and MSD. JD reports honoraria for scientific talks by F. Hoffmann-LaRoche, Janssen-Cilag, Celgene; advisory boards by AbbVie, Amgen, Bristol-Myers Squibb, Janssen-Cilag, Novartis, Gilead; travel grants by Celgene, F. Hoffmann LaRoche, Gilead, Janssen-Cilag, and Mundipharma. ET reports travel grants from Abbvie, Celgene and Gilead. MHe reports honoraria for advisory boards by AbbVie and F. Hoffmann-LaRoche, and travel grants AbbVie and by F. Hoffmann-LaRoche. AMF reports research grants by Celgene and travel grants by AbbVie, F. Hoffmann-LaRoche and Mundipharma. KF reports travel grants from F. Hoffmann-LaRoche. KAK reports research support and honoraria for consultancy or advisory boards by AbbVie, F. Hoffmann-LaRoche and Mundipharma. SB reports grants and personal fees from AbbVie, F-Hoffmann-LaRoche and Janssen, grants from Celgene and Genentech, personal fees from Becton Dickinson and Novartis MR reports research funding from AbbVie, Amgen, F. Hoffmann-LaRoche and Gilead. MK reports honoraria for consultancy or advisory boards by AbbVie and F. Hoffmann-LaRoche. CMW reports research support, honoraria for consultancy or advisory boards and travel support by AbbVie, F. Hoffmann-LaRoche, Genentech, Gilead, GlaxoSmithKline, Janssen-Cilag, Mundipharma and Pharmacyclics. SS reports research support, honoraria for consultancy or advisory boards and travel support by AbbVie, Amgen, Celgene, F. Hoffmann-LaRoche, Genentech, Gilead, GlaxoSmithKline, Janssen-Cilag, Mundipharma, Novartis and Pharmacyclics. BE reports research support and honoraria for consultancy or advisory boards by AbbVie and F. Hoffmann-LaRoche. MHa Research support and honoraria: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, Abbvie. NP, SR and MF report no conflict of interest. Ethics Approval Statement: All patients provided written informed consent. The study was approved by the health authorities and the institutional review board of each participating site, was registered at clinicaltrials.gov (NCT02689141) and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.

Mapping Comorbidity in CLL: Impact on Prognostic Factors, Treatment Patterns and Causes of Death

Introduction In chronic lymphocytic leukemia (CLL), few randomized clinical trials include patients who are older or have significant comorbidity, despite constituting a large proportion of the CLL-population. Therefore, detailed data on the association of specific comorbidities with CLL-prognosis are missing and decisions on treatment and follow-up are poorly informed in comorbid patients. We present data on the association of comorbidity with prognostic factors, treatment patterns and causes of death in patients from the world's largest cohort of unselected CLL-patients. Methods All patients diagnosed with CLL in the CLL-registry (2008-2017) or the Danish Cancer Register (1997-2017) were followed through the Civil Registration System from 1 month after CLL-diagnosis until death, emigration or January 2017. Data from Danish nationwide population-based health registers were linked through personal unique identification numbers. Data on comorbidities based on the modified Charlson Comorbidity Index was attained from the Danish National Patient Register, from 20 years prior to the CLL-diagnosis and until 1 month after. Multimorbidity was defined as ≥ 2 comorbidities. Prognostic baseline data such as Binet Stage, IGHV-status, cytogenetics and β2-microglobuline (B2M) level were available through the CLL-registry. Causes of death were ascertained through the National Register of Causes of Death, further sub-categorized as CLL-related (including CLL, all other malignancies and infections) and CLL-unrelated death. Hazard ratios (HR) for mortality were calculated using Cox regression models, adjusting for age, sex, calendar period (5-year intervals) and internally for all other comorbidities. The association between IGHV-status and overall survival (OS) and treatment-free survival (TFS) was assessed by means of Kaplan-Meier and fully adjusted Cox models, stratifying for age and comorbidity-burden. Results The study included 8055 patients with a median follow-up time of 4.2 years; 59 % were male and the median age at diagnosis was 71 years. Overall 2816 patients (35%) were comorbid and 965 (12%) multimorbid. At diagnosis 818 (10%) patients had a history of chronic heart failure or myocardial infarction, 672 (8%) cerebrovascular disease, 626 (8%) diabetes (type 1 or 2), 620 (8%) chronic pulmonary disease, 399 (5%) peripheral vascular disease, 307 (4%) peptic ulcer, 264 (3%) connective tissue disease, 172 (2%) psychiatric disease, 148 (2%) renal disease, 87 (1%) dementia and 86 (1%) hepatic disease. Elevated B2M (&gt;4.0 mg/L) was more common in comorbid (20%) and multimorbid (24%) patients compared with non-comorbid (11%), while Binet Stage B/C, unmutated IGHV-status and del(17p) were evenly distributed across the groups (18-20%, 31-33% and 6-8%, respectively). Among comorbid patients, 56% died during follow-up, compared with 42% among non-comorbid patients. For comorbid patients, death was more commonly caused by cardiovascular disease (14% vs 6%) or other causes (14% vs 10%), while hematological malignancy was less common (25% vs 34%) compared with non-comorbid patients. Other malignancies (11% vs 13%), infection (34% vs 35%) and cerebrovascular disease (2% vs 2%) were equally common causes of death in the two groups. All individual comorbidities were associated with increased all-cause mortality. Except for connective tissue disease, dementia and chronic pulmonary disease, all comorbidities were associated with increased CLL-related mortality (Fig 1A) and as for CLL-unrelated mortality, only ulcer disease, psychiatric disease, renal disease and connective tissue were not associated with an increase. Unmutated IGHV status was associated with inferior TFS for all patients regardless of age and comorbidity burden (range of HRs 1.47-3.70), while IGHV status was associated with inferior OS for non-comorbid patients only (range of HRs 1.43-1.66). Of comorbid patients who died from CLL-related causes, 59% had not received treatment for CLL, compared with 43% among non-comorbid patients. Conclusions All individual types of comorbidity were associated with increased all-cause mortality and most also with higher CLL-related mortality. Improved management is warranted for comorbid CLL-patients, who should be prioritized in clinical trials of agents with high tolerability to further inform treatment guidelines and reduce CLL-related mortality for these patients. Disclosures Curovic Rotbain: Abbvie: Other: Travel Grant; AstraZeneca: Consultancy, Research Funding; Janssen: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; AstraZeneca: Consultancy, Other: Travel Grant, Research Funding; Sunesis: Consultancy; Acerta: Consultancy; CSL Behring: Consultancy; Roche: Other: Travel Grant; Janssen: Consultancy, Other: Travel Grant, Research Funding; Abbvie: Consultancy, Other: Travel Grant, Research Funding; Gilead: Other: Travel Grant. Da Cunha-Bang:Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; AstraZeneca: Consultancy; Roche: Other: Travel Grant. Frederiksen:Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding; Alexion: Research Funding.

Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Retrospective, Single-Institution Analysis Based on Risk Features and Debulking Strategy with Anti-CD20 Monoclonal Antibody

Background: The treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) has continued to evolve in recent years, offering the patients different therapeutic options. Venetoclax (ven) is a selective, small molecule inhibitor of B-cell receptor-2 (BCL-2) approved by the FDA for patients with newly diagnosed and relapsed/refractory CLL. Stratification based on tumor lysis syndrome (TLS) risk is recommended and may guide debulking strategies. Methods: We retrospectively analyzed 36 patients with relapsed/refractory (RR) CLL who received treatment with ven at the Moffitt Cancer Center between January 2016 and July 2019. Objective response to therapy was determined based on iwCLL. Progression free survival (PFS) and overall survival (OS) were evaluated via Kaplan-Meier method; overall response rate (ORR) and complete response (CR) via Fisher's exact test. Adverse events (AEs) were graded by CTCAEv5. Results: The median age was 58.5 years (28-82). Median follow up was 12.97 months. The vast majority of patients had high risk disease; Chromosomal analysis by Fluorescence In Situ Hybridization (FISH) reported Del17p and Del11q (+/- others, except Del17p) in 18 (50%) patients and 6 (16.7%) patients respectively. Twenty one (58.3%) patients had a TP53 mutation by next generation sequencing. Twenty five (80.6%) patients had unmutated IGHV status, and 24 (79.9%) patients had high or very high CLL-International prognostic Index (CLL-IPI) score. Twenty-four patients (66.7%) had been previously treated with Ibrutinib, 11 of those progressing on it. Further characteristics are described in table 1. Median OS was not reached. Median PFS was 23.93 months, figure 1a. Median duration of response was 25.97 months. The ORR (PR+CR) at the time of analysis was 63.9%, with CR rate of 33.3%, and PR rate of 30.6%. Nine patients (25%) had stable disease (SD), while four patients (11.1%) progressed on treatment. Minimal residual disease (MRD) was evaluated as part of the response assessment in 7 patients (19.4%) by flow cytometry (1 patient) and by clonoSEQ (6 patients), and 4 (11.1%) had achieved undetectable disease. Response rates were also based on risk stratification; OS and PFS were not affected by the presence of TP53 mutation (p=0.1145) as described in figure 1b, IGHV unmutated status, or NOTCH1 mutation. PFS was inferior in patients with high-very high CLL-IPI score (p=0.0414), figure 1c. The presence of bulky lymphadenopathy (≥5 cm) did not affect outcomes (p=0.5772), figure 1d. Reasons for treatment discontinuation were: progressive disease (PD) in 6 (16.7%), MD/patient preference in 5 (13.9%), Richter's transformation in 2 (5.6%), AEs in 1 (2.8%), allogeneic transplant in 1 (2.8%), and death while on treatment in 1 (2.8%) case. Twenty patients (55.6%) were considered to be at intermediate/high risk of developing TLS, of whom 15 (75%) received debulking therapy with rituximab (1), ofatumumab (11), or obinutuzumab (3) prior to ven. Based on the absolute lymphocyte count (ALC), the risk of TLS became low in 12 patients. The use of a debulking monoclonal antibody (MoAb) improved lymphocytosis, but did not impact PFS. Treatment was well tolerated, and was not dependent on the use of debulking MoAb; however, out of the 18 patients (50%) who underwent debulking therapy, 9 (25%) had grade 3/4 toxicities. Neutropenia was the most common grade 3/4 toxicity in all patients, which was seen in 7 (19.4%) patients, and diarrhea was the most common grade 3/4 non-hematologic toxicity, seen in 4 (11.1%) patients; grade 3/4 neutropenia was seen in 4 (57.1%) of those patients who received debulking therapy, while diarrhea was only seen in 1 (25%). No cases of TLS were observed. Ten patients (27.8%) were admitted for ramp up of ven as per physician preference, independent of TLS risk and comorbidities. Conclusion: Venetoclax is a very active agent for R/R CLL with an acceptable toxicity profile. Debulking strategy is a tolerable option for patients with high burden disease and may reduce the incidence of TLS and/or hospitalization. Nonetheless, based on this retrospective study, it does not seem to have a significant impact in outcomes, and it carries a higher risk for potential cumulative toxicity. Disclosures Chavez: Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria. Bello:Celgene: Speakers Bureau. Sokol:EUSA: Consultancy. Nodzon:Pfizer: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: Speaker Fees; Abbvie: Other: Speaker Fees. Pinilla Ibarz:Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau.

Efficacy of Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

Introduction: Chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL) is the most common adult lymphoproliferative disorder in western countries and the B-cell receptor signaling pathway has been shown to be involved in the pathogenesis of CLL/ SLL. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein in downstream signaling for multiple pathways in B cells, promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in the treatment of relapsed and refractory CLL/ SLL. The purpose of our study is to explore and consolidate the efficacy of PI3K inhibitors in patients with relapsed and refractory CLL/SLL. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in the study by Jones et al. and 1:1 in other studies. The I2 statistic for heterogeneity was 82%, suggesting moderate heterogeneity among RCTs. The overall pooled HR for PFS was statistically significant at 0.30 (95% CI: 0.20- 0.47; P &lt; 0.0001). The PFS benefit was observed across all ages and regardless of del 17p or TP53 status; age &lt;65 (HR, 0.35; 95% CI: 0.27- 0.46; P &lt; 0.0001), age ≥65 (HR, 0.32; 95% CI: 0.19- 0.54; P &lt; 0.0001), either del 17p or TP53 cohort (HR, 0.33; 95% CI: 0.21- 0.52; P &lt; 0.0001), and neither del 17p nor TP53 cohort (HR, 0.32; 95% CI: 0.19- 0.54; P &lt; 0.0001). In the subset of patients with CLL treated with idelalisib, the pooled HR for PFS was statistically significant at 0.26 (95% CI: 0.18-0.37; P &lt; 0.0001) and the PFS benefit was observed across all ages, and regardless of del17p or TP53 status and IGHV mutation status; age &lt;65 (HR, 0.32; 95% CI: 0.24- 0.43; P &lt; 0.0001), age ≥65 (HR, 0.26; 95% CI: 0.14- 0.47; P &lt; 0.0001), either del17p or TP53 cohort (HR, 0.29; 95% CI: 0.15- 0.57; P = 0.0003), neither del17p nor TP53 cohort (HR, 0.26; 95% CI: 0.20- 0.35; P &lt; 0.0001), IGHV mutated cohort (HR, 0.29; 95% CI: 0.17- 0.51; P &lt; 0.0001), and IGHV unmutated cohort (HR, 0.25; 95% CI: 0.15- 0.40; P &lt; 0.0001). Conclusions: Our study showed that PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), significantly improved PFS in patients with relapsed and refractory CLL/ SLL regardless of age and poor prognostic features such as del17p or TP53 and IGHV unmutated status, compared to control arm. The efficacy of these drugs must be balanced against the possible side effects. Disclosures No relevant conflicts of interest to declare.

Venetoclax and Ibrutinib for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) - 15-Month Safety, Response and MRD Evaluation: Third Interim Analysis from the Phase II Vision HO141 Trial

Venetoclax and Ibrutinib for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) - 15-Month Safety, Response and MRD Evaluation: Third Interim Analysis from the Phase II Vision HO141 Trial