Prior Chronic Lymphocytic Leukemia Research Articles

Real-World Comparison of Healthcare Costs of Venetoclax-Obinutuzumab Vs. Btki Use Among Elderly U.S. Medicare Beneficiaries with Chronic Lymphocytic Leukemia in the Front-Line (1L) Setting

Background: Since the March 2016 FDA approval of ibrutinib as a front-line therapy in chronic lymphocytic leukemia (CLL), BTK inhibitors (BTKi) used as continuous therapy until progression or toxicity, are increasingly utilized early in the CLL treatment pathway. Conversely, the BCL-2 inhibitor venetoclax, approved for front-line (1L) CLL in May 2019, has been shown to generate durable responses. As a result, venetoclax has gained approval with a fixed treatment duration wherein a venetoclax plus obinutuzumab (VenO) regimen is to be completed after 12 months in the 1L setting. Fixed-duration therapy with a treatment-free remission has the potential advantage of lowering health care costs by avoiding continuous exposure to treatment. However, little real-world evidence has been generated to assess the potential economic benefits of a fixed-duration treatment such as VenO relative to treat-to-progression therapies like BTKis. The objective of this study was to examine healthcare costs before and after completion of the fixed-duration treatment period for VenO relative to that observed for BTKis in a national sample of elderly U.S. Medicare beneficiaries with CLL in the 1L setting. Methods: Our analysis used 2016-2021 100% Medicare Parts A, B, and D claims. Elderly fee-for-service Medicare beneficiaries initiating VenO (VenO group) or an available BTKi treatment (BTKi group) between 6/1/2019 and 6/30/2020 (index date = first prescription fill date) were included in the sample. Additional inclusion criteria for both groups were as follows: (a) ≥66 years old, (b) ≥1 diagnoses of CLL and no diagnoses for other indications of the index agent in the 12-month pre- and post-index period, (c) continuous medical and prescription coverage in the 36 months pre- and 12 months post-index period, (d) no prior CLL treatment in the 36-month pre-index period (i.e., to proxy 1L patients), and (e) continuous medical and prescription coverage from 13 to 18 months after the index date or until death if it occurs earlier (to capture costs after fixed-duration VenO treatment is completed). Healthcare cost measures included all-cause and CLL-related monthly total, prescription, and medical costs. Mean monthly cost measures were captured for both groups over two fixed time periods calculated from the index date: Month 0 to 12 (i.e. proxy for on-treatment period for VenO) and Month 13 to Month 18 (i.e. proxy for off-treatment period for VenO). Risk-adjusted monthly costs were estimated using generalized linear models controlling for differences in sociodemographic and clinical factors between the two groups. Difference-in-Difference method was used to assess reduction in costs across the two fixed time periods. Results: The final sample contained 193 patients (pts) in the VenO group (mean [SD] age 75.6 [5.5] years, 69.4% male, 90.2% White) and 1,577 pts in the BTKi group (mean [SD] age 77.6 [6.3] years, 55.8% male, 92.5% White). Between months 0 to 12, risk-adjusted all-cause monthly total costs were slightly lower for VenO pts ($13,887) than BTKi pts ($14,492) (Table 1). However, during months 13 to 18 the monthly all-cause total costs declined by 67% for VenO pts ($13,887 to $4,462) but only by 10% for BTKi pts ($14,492 to $13,051). Hence, the relative reduction in costs across the two periods was significantly larger for VenO (-$9,425) vs. BTKI (-$1,441) pts (i.e. Difference-in-Difference=-$7,984, p<0.001). Similar patterns were observed for CLL-related costs with the substantially larger reductions in CLL-related total monthly costs (-$9,880 VenO vs. -$1,753 BTKi, p<0.001) for the VenO group relative to BTKi group being primarily driven by the larger reduction in CLL-related monthly prescription costs (-$9,437 VenO vs. -$2,020 BTKi, p<0.001) (Table 1). Conclusions: This real-world study of elderly Medicare beneficiaries with CLL found a large reduction in monthly health care costs in the VenO group after the fixed-duration treatment period of 12 months. This drop was largely driven by the reduction in CLL-related prescription drug costs; however, similar declines were not observed in the BTKi group. Hence, the costs for pts on VenO after the fixed-duration treatment period were approximately $8000 per month lower than the BTKi group. Our study highlights the substantial economic benefits of VenO relative to treat-to-progression therapies like BTKis and carries implications for treatment decision-making CLL.

PD-1 Expression in Lymphoma Cells Mediates Cellular Proliferation By Engaging Phosphatase SHP-1/SHP-2

Introduction: Despite the improved clinical outcomes with novel therapies in patients with chronic lymphocytic leukemia (CLL), Richter transformation (RT) of CLL remains a major clinical challenge. Our group showed a selective response (~40%) with the PD-1 blocking antibody pembrolizumab in patients with RT, particularly after prior exposure to ibrutinib (Ding et al, Blood, 2017). It has been established that PD-1 inhibits cytotoxic T-cell functions via the interaction with its ligands, PD-L1 and PD-L2. However, the role of PD-1 in tumor B-cells is understudied. Here we show the expression and functional implications of the PD-1 signaling axis in B-cell pathobiology. Methods: CLL-involved lymph node (LN) (n=26) and RT (with diffuse large B-cell lymphoma [DLBCL] histology) -involved LN (n=20) samples were tested for PD-1 expression by immunohistochemistry (IHC) (mouse clone NAT105, Abcam). Then, PD-1 expression was examined in 10 lymphoma cell lines and 1 CLL-like cell line (MEC-1) by both flow cytometry (FC) and Western blot (WB) analysis. PD-1 overexpression using pLEX-lentiviral packaging system (Thermo Scientific) was evaluated for its impact on in vitro cell cycle regulation and in vivo tumor growth. CRISPR/CAS9 mediated PD-1 knockdown evaluated on cell growth in MEC-1 and Mino cells. Role of PD-1 was further examined on the regulation of cell signaling pathways using human phospho kinase array kit (R&D) and WB analysis. Additionally, gene expression signatures were evaluated by RNA-seq using pLEX-lentiviral-PD-1 transfected DLBCL cell lines OCI-LY7 and OCI-LY19. Results: PD-1 expression was significantly increased in RT-LN compared to CLL-LN (mean ± SEM in RT vs. CLL, 30.6% ± 4.7% vs. 11.5% ± 2.8%, p<0.001) as determined by IHC. PD-1 expression was highest in patients with RT where the last prior CLL therapy was ibrutinib. To test the role of PD-1 in tumor B-cells, its expression was assessed in lymphoma and CLL cell lines. The expression of PD-1 was found to be variable by both FC and WB analysis, but at very low-levels in DLBCL cell lines OCI-LY7 and OCI-LY19. Constitutive lentiviral (pLEX-PD-1)-mediated overexpression of PD-1 in OCI-LY7 and OCI-LY19 cells led to increased cell growth (1.4 and 1.9 fold, respectively, compared to original lines after 4 days of culturing of equal number of cells), which was further confirmed by cell cycle analysis which showed an increase in S phase by 20.4% (p<0.05) and 24.5% (p<0.05) in OCI-LY7 and OCI-LY19 cells, respectively. When the luciferase+ PD-1 overexpressing OCI-LY7 cells (1X10 6) were injected intravenously into NSG mice, increased tumor growth (p<0.01) was observed by bioluminescence imaging after 22 days of follow-up. PD-1 knockdown in MEC-1 and Mino cells (high basal PD-1 expression) led to significant inhibition of cell growth (85% and 79.5%, respectively, p<0.05). Using phospho-kinase array, an overall decrease of phosphorylation was detected on multiple sites of p53 (S392, S15, S46) and Chk-2 (T68) in PD-1 overexpressing OCI-LY7 and OCI-LY19 cell lines. This finding was further confirmed by WB analyses. In addition, decreased total p53 and increased phosphorylation on both SHP-1 and SHP-2 were found in PD-1 overexpressing OCI-LY7 and OCI-LY19 cell lines. SHP-1 (TPI-1) and SHP-1+SHP-2 (TPI-1+TNO155) inhibitor treatment promoted OCI-LY19 cell death and led to recovery of phosphorylation on ATM, Chk-2 and p53 in these cells. RNA sequencing data in PD-1 overexpressing OCI-LY7 and OCI-LY19 cells revealed increased expression of genes that promote cell cycle progression and DNA replication. Conclusion: Our data showed robust PD-1 expression in patients with Richter transformation from CLL to DLBCL. PD-1 overexpression in DLBCL lymphoma cell lines enhanced cell proliferation in vitro and in vivo. Further investigation identified that PD-1 modified the phosphorylation/function of SHP phosphatases and thereby regulated p53 pathways ( Figure 1). These findings indicate that RT with DLBCL cells have the ability to “hijack” the PD-1 pathway which results in downregulation of p53 mediated DNA repair. This novel finding provides for new strategies to further evaluate the interaction of PD-1 signals with DNA repair pathways and suggest potential novel targets for RT.

Pregnancy in Patents with CLL Systematic Review

Introduction: Chronic Lymphocytic Leukemia (CLL) is a hematologic malignancy characterized by the clonal expansion of non-functional, mature-appearing lymphocytes in the bone marrow, peripheral blood, and lymphoid tissues. While cases of CLL during pregnancy are rare,it is associated with many complications. It was reported that women with CLL are more susceptible to infections due to a weakened immune system; possibly leading to more complications. There is also increased risk of thrombocytopenia, which can increase the risk of bleeding during pregnancy and childbirth. This review aimed at identifying literature available on the complications in CLL and pregnancy as well as the data available on the potential therapeutic strategies. Methods: A scoping review of case reports that discuss pregnant patients who were diagnosed with CLL were isolated. The effects of the disease on pregnancy outcomes regarding both mother and fetus were identified. Animal studies, reviews or non-original articles, and non-English articles were excluded from our study. FDA labels of medications in CLL were reviewed for data on pregnancy and animal outcomes. Information on those medications in pregnant patients were also identified where available. Results: The search strategy across four databases yielded 448 articles. After eligibility assessment, 14 articles were included in the review. Cases were subdivided according to timing of pregnancy relative to CLL diagnosis (diagnosed before pregnancy or during pregnancy at early or late gestational periods). The pre-pregnancy reports were further subclassified based on the presence or absence of infection during pregnancy. None of the cases reported required immediate initiation of CLL therapy and only one case reported mortality post-delivery. This occurred in a patient with Richter transformation and no prior CLL treatments. There were no reported fetal malformations or severe adverse outcomes related to the infants in any of the reported pregnancies ( Figure 2). The included studies provided insights into various aspects of CLL during pregnancy, including patient demographics, diagnosis timing and methods, acquired infections, changes in white blood cell count, treatment approaches, pregnancy outcomes, and complications for both mother and fetus. From the marketed pharmacological alternatives for CLL, most were not studied in pregnant humans with CLL ( Figure 1). However, venetoclax and rituximab have some data in pregnant patients with non-CLL indications. A case reported a pregnant refractory AML patient who received venetoclax with high dose cytarabine and mitoxantrone at 24 weeks of gestation. Bone marrow at 27 weeks showed complete remission and labor was induced at 28 weeks + 5 days after corticosteroid-induced lung maturation. The infant had hyperbilirubinemia, transient B-cell depletion and required ventilation. The baby recovered from all complications, although possible long-term effects are still unclear. The mother underwent allogeneic hematopoietic stem cell transplant. In a 30-year-old female (pregnant at 28 weeks) with primary CNS lymphoma, weekly rituximab was given for 4 weeks with dexamethasone. After delivery through C-section at 31 weeks, the patient started definitive treatment with chemotherapy and autologous transplant. The infant required brief mechanical ventilation and had transient B-cell depletion at delivery until 4 months post-delivery. The baby required a course of post-exposure acyclovir despite not developing an infection. Both mother and baby survived with good outcomes at last follow-up (4 years post-delivery) Conclusion: Despite the rarity of CLL occurrence during pregnancy, there is evident need of further studies and management guidelines in this population. This review provides insights into the possible pregnancy-related concerns in women with CLL at different disease stages. While watchful waiting is generally recommended due to CLL's slow progression, individual evaluation is crucial. If treatment is necessary, delaying therapy until the second or third trimesters may help mitigate the risk of fetal malformations. The increased susceptibility to infections resulting from the combined immunosuppressive effects of CLL and pregnancy should be carefully considered

Richter transformation – retrospective treatment outcomes analysis in Polish Adult Leukemia Study Group

Richter transformation (RT) is defined as developing an aggressive lymphoma in 2–10% of patients suffering from chronic lymphocytic leukemia (CLL). So far, no complex analysis of RT demographics and treatment outcomes has been performed in Poland. Thus, the retrospective analysis of 124 patients with RT from Polish hematology centers was designed. Ninety-nine patients with diffuse large B-cell lymphoma (DLBCL-RT) were identified. The median overall survival (OS) for DLBCL-RT was 17.3 months, while for Hodgkin lymphoma (HL-RT)-21.3 months. In multivariate analysis, the independent factors of worse OS for DLBCL-RT were: prior CLL therapy, ECOG stage ≥2, and elevated serum LDH activity. Patients who proceeded to hematopoietic stem cell transplantation (HSCT) achieved better results. The median OS in allogeneic HSCT recipients was not reached, while in autologous HSCT median OS was 51.3 months. In conclusion, our study represents the largest dataset of patients diagnosed with RT in Poland and confirms its dismal prognosis.

IMMUNOPHENOTYPIC CHARACTERIZATION OF RICHTER SYNDROME DIFFUSE LARGE B‐CELL LYMPHOMA TYPE AND COMPARISON WITH THE ORIGINAL CHRONIC LYMPHOCYTIC LEUKEMIA

Introduction: Biological mechanisms undergoing Richter Syndrome diffuse large B-cell lymphoma type (DLBCL-RS) from a previous chronic lymphocytic leukemia (CLL) arouse a great scientific interest, but the pattern of markers expressed in DLBCL-RS cases has been scarcely studied. Our aim was to immunophenotypically characterize DLBCL-RS and compare it with the prior CLL population. Methods: Retrospective unicenter study of patients histologically diagnosed with DLBCL-RS (DLBCL not otherwise specified subtype) from a prior or concomitant CLL (N = 12). Multiparametric flow cytometry (FCM) and immunohistochemistry (IHC) were used to cluster cases according to their expression level for each marker: bright or moderate (positive), low (dim), or absent (negative). Comparisons were made between CLL and DLBCL-RS in available tissues (lymph node, blood, bone marrow, and others). Results: Median age at DLBCL-RS diagnosis was 74 years (IQR 65-79) and 42% were males. Three cases were concomitantly diagnosed with CLL and DLBCL-RS; the median time of transformation in the remaining 9/12 was 76 months (IQR 51-112), and all of them had received at least 1 therapeutic line for the CLL (median 2). Clonal relationship was demonstrated in 9/10 cases with available information. Figure 1 shows the most relevant phenotypic comparisons between CLL and DLBCL-RS populations. Although phenotypic variability was seen for all antigens, some of them showed tendency to increase or decrease their pattern of expression. CD19, CD20, CD5, CD79b, and CD200 tended to lose expression in the DLBCL-RS phase (3/5 DLBCL-RS CD20 negative cases had received anti-CD20 therapy during the 12-month period prior to transformation). On contrary, CD38 and Ki67 were constant in the increasing of expression. Other markers such as CD23, CD43, CD22, and CD11c presented higher variability. One case showed CD10 dim expression of the DLBCL-RS, while it remained negative in the other 11/12. The light-chain restriction was the same in 10/12 (κ:λ ratio of 1.5:1); 1/12 presented a switch from κ to λ, and 1/12 DLBCL-RS showed negativity for κ/λ, when κ was restricted in the CLL phase. p53 expression was available in 7 cases, being negative in CLL tissue in all of them: 3/7 retained p53 negativity in the DLBCL-RS, while 4/7 showed p53 overexpression after transformation. Treatment for the DLBCL-RS was initiated in 8/12 cases, being 92% death at data cut-off date (median follow-up 6.5 months from DLBCL-RS diagnosis, IQR 2.4–9.7). Keywords: diagnostic and prognostic biomarkers, pathology and classification of lymphomas, tumor biology and heterogeneity No conflicts of interests pertinent to the abstract.

Initial results of a multicenter phase 2 study of venetoclax in combination with R‐CHOP (VR‐CHOP) for patients with Richter Syndrome

Introduction: We previously reported promising efficacy for venetoclax (V) plus da-R-EPOCH (VR-EPOCH) for 26 patients (pts) with CLL who developed Richter Syndrome (RS), with a CR rate of 50% and median OS of 19.6 mo.; however, hematologic and infectious complications were common (Davids et al., Blood, 2022). We hypothesized that de-intensifying the chemoimmunotherapy backbone while keeping the venetoclax could potentially preserve efficacy while mitigating the toxicities observed with this approach. Here, we report for the first time on an ongoing study of VR-CHOP in RS. Methods: This is a single-arm, phase 2, investigator sponsored trial of VR-CHOP for RS (NCT03054896) open at 3 US sites. We treated pts with CLL and biopsy-confirmed DLBCL with R-CHOP for 1 cycle, then after count recovery with accelerated inpatient daily V ramp-up (20/50/100/200/400 mg), then VR-CHOP outpatient for up to 5 additional 21d cycles (V 400 mg qd, d1–10 of each cycle) with mandatory G-CSF support. Responders could then receive daily V 400 mg qd maintenance in 28d cycles or elect to come off study for alloHCT. Response was by Lugano criteria with PET/CT, toxicity by CTCAE v4.03. Results: As of 24 Feb 2023, 27 pts have started study treatment. Median age: 72 yrs (range 42–80), 37% had del(17p) or TP53 mut, 26% had NOTCH1 mut. Median # prior CLL treatments was 1 (range 1–9), including 44% post-BTKi and 17% post-V; 4 pts (15%) had prior treatment for RS. Median # of VR-CHOP cycles to date in this ongoing study is 4 (range 1–6). ≥Gr 3 heme toxicity included: neutropenia (36%), anemia (32%), thrombocytopenia (40%). Additional ≥Gr 3 toxicities in ≥10% of pts included: febrile neutropenia (32%) and peripheral neuropathy (12%). No TLS occurred with daily V ramp-up after 1 cycle of R-CHOP. Two pts on active treatment have not yet reached the first response eval. In the remaining 25 pts, ORR: 68% (17/25), CR: 48% (12/25). 7 pts have died: 4 due to PD (including 2 prior to starting V) and 3 due to infection (n = 2 sepsis, n = 1 COVID-19). 8 pts with initial CLL marrow involvement had re-staging marrows, and 88% (7/8) were uMRD for CLL by flow at 10–4. 7 pts in remission electively went to alloHCT. With a median follow-up of 6.1 mo (range 0.1–21.4), median PFS is 7.2 mo (Figure A), median OS is 19.5 mo (Figure B). The research was funded by: Genentech Keywords: Chemotherapy, Chronic Lymphocytic Leukemia (CLL), Combination Therapies Conflicts of interests pertinent to the abstract. M. S. Davids Consultant or advisory role: AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb, Eli Lilly, Genentech, Genmab, Janssen, Merck, Mingsight Pharmaceuticals, Ono Pharmaceuticals, Secura Bio, Takeda, and TG Therapeutics Honoraria: Aptitude Health, AXIS Medical Education, BioAscend, Curio Science, Medscape Education, PeerView Institute for Medical Education, Physician’s Education Resource, PlatformQ Health Education, Plexus Communications, and Research to Practice Research funding: AbbVie, Ascentage Pharma, AstraZeneca, Genentech, Novartis, Secura Bio, and TG Therapeutics K. A. Rogers Consultant or advisory role: AbbVie, AstraZeneca, Genentech, Pharmacyclics, Janssen, Beigene, LOXO/Lilly Honoraria: AstraZeneca, Janssen Research funding: Genentech, AbbVie, Janssen, and Novartis Educational grants: AstraZeneca N. Jain Consultant or advisory role: Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, BMS, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, Beigene, Cellectis, MEI Pharma, Ipsen, CareDX, MingSight, Novalgen Research funding: Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, Pfizer, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Fate Therapeutics, Kite/Gilead, Mingsight, Takeda, Medisix, Loxo Oncology, Novalgen, Dialectic Therapeutics, Newave, TransThera Sciences, Novartis, Carna Biosciences, Sana Biotechnology, Kisoji Biotechnology J. R. Brown Consultant or advisory role: Abbvie, Acerta/Astra-Zeneca, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, Kite, Loxo/Lilly, MEI Pharma, Numab Therapeutics, Pfizer, Pharmacyclics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics P. A. Thompson Consultant or advisory role: Janssen, AbbVie, Adaptive Biotechnologies, Beigene, Lilly, Genentech Research funding: AbbVie, Pharmacyclics, Lilly and Adaptive Biotechnologies

Humoral Response to mRNA Vaccines BNT162b2 and mRNA-1273 COVID-19 in Chronic Lymphocytic Leukemia Patients

Humoral Response to mRNA Vaccines BNT162b2 and mRNA-1273 COVID-19 in Chronic Lymphocytic Leukemia Patients

Clinical Outcome and Prognostic Factors of Patients with Richter's Syndrome: Retrospective Multicenter Study of the Spanish Chronic Lymphocytic Leukemia (CLL) Study Group (GELLC)

Richter syndrome (RS), the development of diffuse large B-cell lymphoma (DLBCL) in the context of CLL, is an uncommon complication with a dismal prognosis. Currently, data on biological and clinical features, and factors predicting the outcome of patients are scarce, and there is still no consensus on the best therapeutic approach for these patients (pts). The aim of this study was to analyze the presenting characteristics, treatment outcomes, and factors predicting for survival in a series of pts with RS from a large population-based cohort of the Spanish CLL Study Group (GELLC).Pts diagnosed with RS during 1988 - 2017 were retrospectively identified in eleven centers of the GELLC group. Only cases with confirmed biopsy-proven RS during follow-up were included. Clinical-biological features at diagnosis of RS, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status detected by in situ hybridization, cell of origin (COO) analyzed by immunohistochemistry, International Prognostic Index score (IPI) and the RS score (Tsimberidou AM et al, J Clin Oncol, 2006), as well as treatment and outcomes, were analyzed.One hundred and twenty-three pts with transformation of CLL to high-grade lymphoma were identified, including 108 classical DLBCL RS, 14 pts with Hodgkin lymphoma (HL), and one case of plasmablastic lymphoma. Median age of the whole series was 66 years (range, 31 to 92 years), and 64% were men. For the DLBCL RS, median time from the diagnosis of CLL to RS development was of 4.7 years (range, 0-24.8 years, with 9 simultaneous diagnosis of CLL and RS), and the median number of prior therapies for CLL/SLL was 1 (range, 0-7). The main clinical characteristics of the pts are shown in table 1. EBV was detected in 12/36 (33%) cases with classical RS and in 9/11 (82%) of patients with HL variant. According to COO the majority of RS tested (20 of 24, 83%) had a non-germinal center phenotype, whereas 19/23 (83%) cases were clonally related to the preceding CLL. Twelve out of 43 pts had 17p deletion or mutation of TP53 in the CLL clone at the time of RS diagnosis.Among the 108 patients with DLBCL RS, data on the treatment for RS was available in 99 patients. Twenty-one patients did not received treatment due to frailty, comorbidities, or poor performance status. Of the 78 patients that were treated for RS, 46 patients received chemoimmunotherapy, mainly R-CHOP (n=44), 29 patients chemotherapy (most commonly CHOP and purine analogue-based therapy), and others (n=3). The overall response rate for the 99 treated patients was 44% (chemotherapy, 24%; chemoimmunotherapy, 60%; P=0.003). A total of 13 patients underwent stem-cell transplantation (SCT), allogeneic SCT (n=7) or autologous SCT (n=6).After a median follow-up for surviving patients of 36 months (range 0.8-160 months), median overall survival (OS) from the time of transformation of CLL to high grade lymphoma was 7.3 months for the entire cohort, 5.7 months for DLBCL RS patients, and 30.8 months for patients with HL variant (P=0.07). Factors associated with shorter OS in the DLBCL RS series included, ECOG PS >1, Hb level < 10 g/dL, platelet count < 100x109/L, LDH > 1.5 UNL, β2-microglobulin > 3mg/dL, prior CLL therapies >1, p53 positive determined by IHQ, and 17p deletion or mutation of TP53 determined in the CLL clone. RS score was also predictive for OS (median OS of 59.5 months [0-1 points], 5.4 months [2 points], 2 months [3 points], and 3 months [4-5 points], p= 0.006); on the contrary, IPI was not discriminative for OS in this series. In addition, RS clonally related presented a median OS of 5.9 months in comparison with 74.8 months for the clonally unrelated RS (p= 0.071). Finally, patients treated with chemoimmunotherapy combinations presented a median OS of 35.4 months, and the 13 patients that could consolidated the response obtained with SCT (autologous or allogeneic SCT) obtained a median OS of 59.5 months.Although clinical outcome of patients with RS is generally poor, chemoimmunotherapy combinations are effective and obtain durable responses in a proportion of patients. RS score and TP53 disruption are predictive of survival. Finally, pts attaining a response should be considered for SCT. Further clinical development with novel promising treatment options is warranted. [Display omitted] DisclosuresDelgado:Abbvie, Jansen, Gilead, Roche: Consultancy, Speakers Bureau.

Neutropenia analysis of venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: Pooled data from VENICE-I and -II Phase IIIb trials.

e20011 Background: Neutropenia is a common hematologic Grade (Gr) 3+ adverse event (AE) recorded in patients with chronic lymphocytic leukemia (CLL) receiving venetoclax (VEN). In this analysis, we evaluated fixed duration VEN monotherapy given to patients with relapsed or refractory (R/R) CLL with and without pre-existing Gr3+ neutropenia. Methods: This post-hoc analysis pooled data from patients in the ongoing Phase 3b trials VENICE-I and VENICE-II with R/R CLL who had received ≥1 dose of VEN monotherapy (ramp-up to 400 mg QD). Gr4 hematologic AEs and Gr3+ neutropenia ( &lt; 1000 cells/mm3) with infection or fever were managed using dose interruption/reduction. Granulocyte colony stimulating factor (G-CSF) was used in Gr3+ neutropenia. Results: At data cutoff (June 30, 2019), 44/468 (9%) patients had Gr3+ neutropenia at baseline (BL; Gr3+ neutropenia group), 80% of whom received G-CSF during the study vs 38% of those with &lt; Gr3 neutropenia at BL ( &lt; Gr3 neutropenia group). Median on-study duration for VEN was 20.2 months (range: 0.1–36.1). Median number of prior CLL therapies was 2 for both groups (range: 1–10). Serious infections were experienced by 10/44 (23%) and 69/424 (16%) of patients in the Gr3+ and &lt; Gr3 neutropenia groups, respectively. The most common AEs leading to discontinuation overall were second primary malignancies (13/468; 3%). 5/468 (1%) patients in the total population discontinued due to neutropenia/febrile neutropenia. One case of Gr5 infection with concomitant Gr3 neutropenia was reported in the &lt; Gr3 neutropenia group post-VEN discontinuation. See Table. Conclusions: In this large post-hoc analysis, discontinuation due to neutropenia was rare (1%) in the overall population and accounted for 3/11 AE discontinuations in the Gr3+ neutropenia group; 10 patients had a serious infection. Patients with pre-existing neutropenia can be managed on VEN, though concurrent use of G-CSF is likely to be required. Additional data to follow. Clinical trial information: NCT02756611; NCT02980731 . [Table: see text]

A Phase Ia/Ib Study Exploring the Synthetic Lethality of the Orally Administered Novel BTK Inhibitor, Dtrmwxhs-12 (DTRM-12), in Combination with Everolimus and Pomalidomide in Patients with Relapsed/Refractory CLL, DLBCL or Other B-Cell Lymphomas

A Phase Ia/Ib Study Exploring the Synthetic Lethality of the Orally Administered Novel BTK Inhibitor, Dtrmwxhs-12 (DTRM-12), in Combination with Everolimus and Pomalidomide in Patients with Relapsed/Refractory CLL, DLBCL or Other B-Cell Lymphomas

PreVent-ACaLL Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping

Background Patients with Chronic Lymphocytic Leukemia (CLL) have an increased risk of infections both prior to and upon treatment. Infections are the major cause of death for these patients, the 5-year incidence of severe infection prior to treatment is approximately 32 % with a 30-day mortality of 10 % (Andersen et al., Haematologica, 2018). Chemoimmunotherapy is still 1st line standard of treatment for patients without del17p or TP53 mutation despite association with neutropenia, immunesuppression and infections. The combination of BTK inhibitors and the bcl-2 inhibitor venetoclax has demonstrated synergy in vitro and in vivo, while translational data indicate that the CLL-related immune dysfunction can be improved on treatment with reduced risk of infections. Employing the Machine-Learning based CLL treatment infection model (CLL-TIM) that we have developed, patients with a high (&gt;65%) risk of infection and/or need of CLL treatment within 2 years of diagnosis can be identified (CLL-TIM.org). The significant morbidity and mortality due to infections in treatment-naïve CLL warrants trials that challenge the dogma of only treating symptomatic CLL. Thus, we initiated the randomized phase 2 PreVent-ACall trial of 12 weeks acalabrutinib + venetoclax to reduce risk of infections. Methods Design and statistics A phase 2, randomized, open label, multi-center clinical trial for newly diagnosed patients with CLL. Based on the CLL-TIM algorithm, patients with high risk of severe infection and/or treatment within 2 years from diagnosis can be identified. Approximately 20% of newly diagnosed CLL patients will fall into this high-risk group. First patient in trial planned for September 2019, primary outcome expected in 2021. Only patients identified as at high risk, who do not currently fulfil IWCLL treatment criteria are eligible. Patients will be randomized between observation in terms of watch&amp;wait according to IWCLL guidelines or treatment. Primary endpoint Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm after 24 weeks (12 weeks after end of treatment). Study treatment Acalabrutinib 100 mg BID from cycle 1 day 1 for 12 weeks. Venetoclax, ramp up during the first five weeks starting cycle 1 day 1, thereafter 400 mg once daily for a total of 12 weeks counted from cycle 1 day 1. Patients A sample size of 25 patients in each arm, 50 patients in total. Major inclusion criteria CLL according to IWCLL criteria ≤1 year prior to randomizationHigh risk of infection and/or progressive treatment within 2 years according to CLL-TIM algorithmIWCLL treatment indication not fulfilledAdequate bone marrow functionCreatinine clearance above 30 mL/min.ECOG performance status 0-2. Major exclusion criteria Prior CLL treatmentRichter's transformationPrevious autoimmune disease treated with immune suppressionMalignancies other than CLL requiring systemic therapies or considered to impact survivalRequirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonistsHistory of bleeding disorders, current platelet inhibitors / anticoagulant therapyHistory of stroke or intracranial hemorrhage within 6 months Trial registry number EUDRACT NUMBER: 2019-000270-29 Clinicaltrials.gov number: NCT03868722 Perspectives: As infections is a major cause of morbidity and mortality for patients with CLL prior to any treatment, we aim at changing the natural history of immune dysfunction in CLL. The PreVent-ACaLL trial includes an optional extension into a phase 3 part with the primary outcome of grade ≥3 infection-free, CLL treatment-free survival two years after enrollment to address the unmet need of improved immune function in CLL for the first time. Figure Disclosures Da Cunha-Bang: AstraZeneca: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; Roche: Other: Travel Grant. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Österborg:BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Kancera AB: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Other: Travel grant, Research Funding. OffLabel Disclosure: acalabrutinib and venetoclax in combination for CLL.

Clinical characteristics and outcomes of Richter transformation: experience of 204 patients from a single center.

The natural history, prognostication and optimal treatment of Richter transformation developed from chronic lymphocytic leukemia (CLL) are not well defined. We report the clinical characteristics and outcomes of a large series of biopsy-confirmed Richter transformation (diffuse large B-cell lymphoma or high grade B-cell lymphoma, n=204) cases diagnosed from 1993 to 2018. After a median follow up of 67.0 months, the median overall survival (OS) was 12.0 months. Patients who received no prior treatment for CLL had significantly better OS (median 46.3 vs. 7.8 months; P<0.001). Patients with elevated lactate dehydrogenase (median 6.2 vs. 39.9 months; P<0.0001) or TP53 disruption (median 8.3 vs. 12.8 months; P=0.046) had worse OS than those without. Immunoglobulin heavy chain variable region gene mutation, cell of origin, Myc/Bcl-2 double expression and MYC/BCL2/BCL6 double-/triple-hit status were not associated with OS. In multivariable Cox regression, elevated lactate dehydrogenase [Hazard ratio (HR) 2.3, 95% Confidence Interval (CI): 1.3-4.1; P=0.01], prior CLL treatment (HR 2.0, 95%CI: 1.2-3.5; P=0.01), and older age (HR 1.03, 95%CI: 1.01-1.05; P=0.01) were associated with worse OS. Twenty-four (12%) patients underwent stem cell transplant (20 autologous and 4 allogeneic), and had a median post-transplant survival of 55.4 months. In conclusion, the overall outcome of Richter transformation is poor. Richter transformation developed in patients with untreated CLL has significantly better survival. Stem cell transplant may benefit select patients.

Psoas Abscess Due to Mycobacterium avium in A Patient with Chronic Lymphocytic Leukemia－Case Report and Review.

Infections may constitute a serious complication in patients with chronic lymphocytic leukemia (CLL). New treatment agents including obinutuzumab and ibrutinib have improved the progression-free survival in CLL, and data suggest a similar overall infection risk and a limited risk of opportunistic infections when compared to standard chemo-immunotherapy. Nevertheless, cases of opportunistic infections including non-tuberculous mycobacterial (NTM) in CLL patients have recently been published. We present a case of a 74-year old man with extensive prior CLL treatment history, including most recently obinutuzumab. He developed an abscess of the psoas muscle and inguinal lymphadenopathy. An inguinal node biopsy specimen showed infection with Mycobacterium avium, confirmed by broad-spectrum mycobacterial PCR, M. avium-specific PCR, and mycobacterial culture. This case and our literature review suggest that physicians should be aware of opportunistic infections in patients with CLL. Diagnostic differentiation from CLL disease progression, Richter’s transformation to aggressive lymphoma, and secondary malignancy relies on histological and appropriate microbiological studies from biopsy material of affected organs. Infection prophylaxis in CLL should be considered, including vaccinations and intravenous immune globulin replacement.

Clinical Characteristics and Outcomes of Chronic Lymphocytic Leukemia Patients with Richter Transformation

Introduction: Richter transformation (RT) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Most studies on the management of RT were either small retrospective series or early phase non-randomized trials before the era of novel agents. The natural history, prognostication and optimal treatment of patients with RT remain undefined. Here we report the clinical characteristics and outcomes of a large series of RT from a single center. Methods: Biopsy-confirmed RT (limited to non-Hodgkin lymphoma) diagnosed from 4/1993 to 4/2018 were identified from the Mayo Clinic CLL database. Clinical characteristics, treatment information and follow-up data were abstracted by chart review. Overall survival (OS) was defined as time from RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analysis was done in SAS 9.4. Results: A total of 204 patients with CLL who developed RT were identified. The median age at CLL diagnosis was 62 years (range 22-85), and 148 (73%) were male. The median time to transformation was 4.7 years (range 0-34.5). Prior to RT, 68 (33.3%) patients received no treatment for CLL, 109 (53.4%) received chemoimmunotherapy (CIT) only, and 27 (13.2%) received at least one novel agent (idelalisib, ibrutinib, or venetoclax) for CLL. The median lines of CLL therapy prior to RT was 2 (range 0-13). The median age at RT diagnosis was 69 years (range 30-88). Pathology of RT was DLBCL and high grade B-cell lymphoma in 193 (94.6%) and 11 (5.4%) patients, respectively. The median LDH was 306 IU/L (range 99-9000). 62/125 (49.6%) patients had bulky disease (≥ 5 cm), and the median PET SUVmax was 13.9 (range 2.9-30.0). 45/131 (34.4%) patients had del(17p) or TP53 mutation, 12 (9.2%) had del(11q), 21 (16.0%) had trisomy 12, 27 (20.6%) had del(13q), and 25 (19.1%) had normal FISH. The CLL and RT were clonally related in 12/21 (57.1%) patients. For the transformed lymphoma, cell of origin by Han9s algorithm was germinal center B cell-like (GCB) and non-GCB in 31/100 (31.0%) and 69/100 (69.0%) patients, respectively. EBV was positive in 14/52 (26.9%) patients. The median Ki-67 was 80% (range 10-100). Myc and Bcl-2 were positive by IHC in 31/43 (72.1%) and 83/103 (80.6%) patients, respectively; 27/56 (48.2%) were double-expressors. MYC, BCL2, and BCL6 rearrangement was positive by FISH in 18/68 (26.5%), 10/34 (29.4%), and 4/31 (12.9%) patients, respectively; 8/66 (12.1%) were double/triple-hit. The most common first-line treatment (Table 1 notes) of RT was R-CHOP-like regimen (n=114, 65.5%). Other treatments included R-EPOCH-like (n=6, 3.4%), high-intensity chemotherapy (n=15, 8.6%), novel agents (eg, ibrutinib, venetoclax, pembrolizumab; n=19, 10.9%), other chemotherapy (n=12, 6.9%), and palliative therapy (n=8, 4.6%). Response to first-line treatment was CR in 57 (38.0%), PR in 33 (22.0%), SD in 18 (12.0%), and PD in 42 (28.0%) patients. The median OS of the entire cohort after RT diagnosis was 12.0 months. The median OS for patients who received no prior CLL treatment, CIT only or at least one novel agent for CLL were 65.5, 7.3, and 12.0 months, respectively (P Conclusions: Over two thirds of RT were the non-GCB subtype, and about half were Myc/Bcl-2 double expressors. Patients who developed RT without prior CLL therapies had a significantly better OS. In contrast, patients who had received prior CLL therapies had poor outcomes. Myc/Bcl-2 double expressor and MYC/BCL2/BCL6 double/triple hit status had no impact on OS. Disclosures Kenderian:Humanigen: Research Funding; Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding. Kay:Infinity Pharm: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Agios Pharm: Membership on an entity9s Board of Directors or advisory committees; Morpho-sys: Membership on an entity9s Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees; Acerta: Research Funding; Cytomx Therapeutics: Membership on an entity9s Board of Directors or advisory committees; Pharmacyclics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity9s Board of Directors or advisory committees. Parikh:Janssen: Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding; Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding. Ding:Merck: Research Funding.

Outcome of Patients with Aggressive B Cell Lymphomas Who Receive Second-Line Salvage Immunochemotherapy Following Treatment Failure of Intensive First-Line Immunochemotherapy

Outcome of Patients with Aggressive B Cell Lymphomas Who Receive Second-Line Salvage Immunochemotherapy Following Treatment Failure of Intensive First-Line Immunochemotherapy

Outcomes of Patients with Relapsed/Refractory Double Expressor B Cell Lymphoma As Defined By Multicenter Pathology Review Treated with Ibrutinib Monotherapy

Outcomes of Patients with Relapsed/Refractory Double Expressor B Cell Lymphoma As Defined By Multicenter Pathology Review Treated with Ibrutinib Monotherapy

Risk Factors Associated with Richter's Transformation in Patients with Chronic Lymphocytic Leukemia

Background Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Roughly, 2-10 % of patients with CLL develop RT most often as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL).Aim This study aimed to assess the incidence rate and risk factors for RT for patients with CLL in a nationwide cohort. Furthermore, we want to assess prognostic risk factors for patients with RT.Methods All patients diagnosed with CLL in Denmark between 2008 and 2016 were included in this study. Clinical data was retrieved from the Danish National CLL Registry (DCLLR), whereas all histologically verified DLBCL, HL and/or transformation diagnoses for patients with CLL were retrieved from the Danish National Pathology Registry. Patients were followed from date of CLL diagnosis until date of RT, death or end of follow-up, whichever came first. The time to RT was estimated as cumulative incidence considering death as a competing risk. Stepwise Cox analysis with backward elimination was applied to identify independent risk factors for RT in patients with CLL.Results A total of 3771 CLL patients were identified, and followed for 14165 person-years. With a median follow-up of 4.3 (IQR (2.4;6.6)) years, 120 (3%) CLL patients had a transformation diagnosis, of which 4 patients were excluded due to misdiagnosis. DLBCL accounted for 78/116 (67%) cases, HL for 15/116 (13%) cases and one patient presented with both DLBCL and HL. In the remaining 22/116 (19%) cases the subtype of the transformation was either unspecified or unclassified RT. The median time to RT was 3.4 (IQR (1.8;5.7)) years from CLL diagnosis and the median overall survival (OS) after development of RT was 4.9 (IQR (0.7;8.4)) years. The cumulative incidence of RT, calculated by Aalen-Johansen estimator, at 5 and 8 years post-CLL diagnosis were 3.3% and 7.9% respectively (Figure 1). The annual crude incidence rate of RT was approximately 0.7% per year for all CLL patients. In all, 918 (24%) patients received CLL-related treatment, of whom 59 (6.4%) patients developed RT, resulting in a cumulative incidence of RT of 7% after 5 years and 11% after 8 years. At the time of CLL diagnosis, patients treated for CLL prior to RT diagnosis had a worse median OS (1.49 years) compared to RT patients who were untreated for CLL (6.16 years). In the univariate analysis, RT was significantly associated with male gender, advanced Binet stage (B or C), unmutated IGHV status (CLL-U), elevated beta-2-microglobulin (>3.5 mg/L) and elevated lactate dehydrogenase (>205 U/L). Of cytogenic aberration, deletion 13q (del(13q)) had a protective effect on the risk of RT, whereas deletion 11q (del(11q)) and deletion 17p (del(17p)) increased the risk. In the multivariable model, advanced Binet stage (HR 2.86 (1.82;4.51), p<0.001), del(17p) ((HR 3.74 (2.12;6.61), p<0.001) and CLL-U ((HR 2.30 (1.46;3.63), p<0.001) showed an independent correlation with development of RT. ZAP70 and CD38 were excluded from statistical analyses due to incomplete data and high inter-laboratory variation. Among RT patients, CLL-U, trisomy 12 and del(17p) at CLL diagnosis as well as ECOG Performance Status (PS) (i.e. PS≥1) at time of RT diagnosis correlated with poor OS in univariate analysis. Both del(17p) and PS≥1 were independently associated with an increased risk of death in a multivariable analysis (HR 2.9, (1.1;7.7), p=0.04 and HR 3.0, (1.0;3.1), p=0.05, respectively).Conclusions To the best of our knowledge, we here report the largest study on RT assessing nationwide data of consecutive patients diagnosed with CLL. The incidence of RT in this unselected population was 3.3% after 5 years while the median OS for patients from time of RT was 4.9 years. Advanced Binet stage, del(17p) and CLL-U were significantly and independently associated with an increased risk of RT. Del(17p) at CLL diagnosis and PS≥1 at RT diagnosis were significant predictors for death for patients with RT. For patients diagnosed with RT prior to any CLL treatment, a less severe disease course with a median OS of 6.16 years was demonstrated. Contrary, the median OS for patients receiving prior CLL treatment was 1.49 years. Thus, assessment of different treatment options for patients developing RT based on whether they have received prior CLL treatment or not is warranted. [Display omitted] DisclosuresBen-Dali:Rigshospitalet: Research Funding. Hleuhel:Rigshospitalet: Research Funding. Brieghel:Arvid Nilson's Fund: Research Funding; Rigshospitalet, Denmark: Research Funding. Niemann:Danish Cancer Society: Research Funding; Novo Nordisk Foundation: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy.

Chronic Lymphocytic Leukemia (CLL) Transformed into Hodgkin Lymphoma (HL): Clinical Characteristics and Outcomes from a Large Multi-Center Collaboration

Chronic Lymphocytic Leukemia (CLL) Transformed into Hodgkin Lymphoma (HL): Clinical Characteristics and Outcomes from a Large Multi-Center Collaboration

PD-1 Overexpression in Richter's Transformation (RT) and Aggressive Chronic Lymphocytic Leukemia (CLL) after Progression on Ibrutinib Increases Bcl-2 Expression Via Akt/mTOR Pathway

Introduction: Given the established role of PD-1 in mediating immune suppression in chronic lymphocytic leukemia (CLL), we tested and reported the efficacy of PD-1 blocking antibody pembrolizumab in relapsed and transformed CLL patients. A selective response of pembrolizumab (~40%) in patients with RT, particularly after prior ibrutinib, was observed (Ding, Blood, 129:3419). Correlative analysis showed PD-1 expression in tumor B-cells of patients with RT and aggressive CLL after progression on ibrutinib. PD-1, an inhibitory receptor expressed on CLL T-cells, inhibits the immune synapse and cytotoxic T cell functions via the interactions with its ligands. However, the expression pattern and role of PD-1 in tumor B-cells is not well defined. In this study we investigated the functional implication of the PD-1 signaling axis in B-cell pathobiology in CLL and RT patients.Methods: 26 CLL-involved lymph node (LN) and 20 RT-involved LN were tested for PD-1 expression by immunohistochemistry (mouse clone NAT105, Abcam). For in vitro study, we checked PD-1 expression in 11 lymphoma cell lines and 1 CLL cell line by both flow cytometry and Western blot (WB) analysis. Effect of PD-1 knockdown using CRISPR/Cas9 system (Addgene) and over-expression of PD-1 using pLEX-lentiviral (Thermoscientific) or pRetro-retroviral (Clonetech) system were evaluated on pro-survival and apoptotic signaling pathways by Western blot analysis. Gene expression signatures in CLL and RT patients were also evaluated by Illumina-based RNA sequencing using FFPE-nodal tissue obtained by clinical biopsy (Tempus Labs; Chicago, IL).Results: The expression of PD-1 was significantly increased in RT-LN compared to CLL-LN. (mean ± SEM in RT vs. CLL, 30.6 ± 4.7 vs. 11.5 ± 2.8, p < 0.001). PD-1 expression was highest in patients with RT where the immediate prior CLL therapy was ibrutinib (Figure 1A). Among all cell lines tested for PD-1 expression, the expression of PD-1 by WB and flow was highest in Mino (mantle cell lymphoma line), followed by moderate expression in Jvm2 (B-PLL line) and Mec1 (CLL line), and very low-level expression in both Jeko-1 (B-NHL line) and lymphoma line ‘Karpas299‘. CRISPR/Cas9 mediated depletion of PD-1 in Mino cells inhibited constitutively active Akt, p70S6K and mTOR pathway, accompanied by significant downregulation of the anti-apoptotic proteins, Bcl-2, Mcl-1 and XIAP, but P-ERK1/2 was not affected. Constitutive lentiviral (pLEX-PD-1)-mediated overexpression of PD-1 in Jeko-1 and doxycycline regulated inducible retroviral (pRetro-PD-1) mediated overexpression of PD-1 in Karpas299 activated Akt, mTOR and p70S6K pathway. Overexpression of PD-1 in Jeko-1 significantly increased Bcl-2 and Mcl-1 and in Karpas299 increased Bcl-2, Mcl-1 and XIAP expression (Figure 1B). A parallel genetic analysis using RNA sequencing was performed on 5 nodal tissues involved by either RT or progressive CLL after these patients developed clinical progression after prior ibrutinib therapy. In all 5 patients, overexpression of PD-1 was associated with increased expression of Bcl-2 and mTOR regardless of the genetic mutations detected (including TP53, ATM, BTK, NOTCH1, XPO1, SF3B1, TET2 etc). However, in 2 patients who received prior chemoimmunotherapy, similar overexpression of gene signature was not observed by RNA sequencing analysis, alternative pathways including Met or NFkB overexpression was detected. Given these clinical and laboratory findings, we have treated 2 RT patients with a combination of BTK and Bcl-2 inhibitors (ibrutinib and venetoclax, respectively) whose CLL transformed after prior ibrutinib. Significant reduction of tumor burden was observed in both cases with one complete response and one mixed response.Conclusion: An increased expression of PD-1, Akt/mTOR and Bcl-2 gene signature was first observed in RT patients after prior ibrutinib therapy. PD-1 overexpression in the tumor B-cells of RT and progressive CLL patients likely regulate AKT/mtOR to upregulate Bcl-2. Targeting both BTK and Bcl-2 pathways in addition to PD-1 blockade appear to be a promising strategy to treat these aggressive diseases. DisclosuresParikh:Gilead: Honoraria; Janssen: Research Funding; Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AstraZeneca: Honoraria, Research Funding. Kenderian:Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding. Ansell:Takeda: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Merck & Co: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding. Kay:Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Ding:Merck: Research Funding.

Long-Term Evaluation of Efficacy and Safety of Ofatumumab Added to Fludarabine & Cyclophosphamide in Subjects with Relapsed Chronic Lymphocytic Leukemia: Final Analysis of Complement 2 Trial

Long-Term Evaluation of Efficacy and Safety of Ofatumumab Added to Fludarabine & Cyclophosphamide in Subjects with Relapsed Chronic Lymphocytic Leukemia: Final Analysis of Complement 2 Trial