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Purpose: Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL. Experimental Design: Responses to PI3K-δi, PI3K-γi, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compartments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naïve and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib. Results: We demonstrate the essential roles of PI3K-δ for CLL B-cell survival and migration, of PI3K-γ for T-cell migration and macrophage polarization, and of dual inhibition of PI3K-δ,γ for efficacious reduction of leukemia burden. We also show that samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in a xenograft model, irrespective of BTK mutations. In support of this, we report a patient with ibrutinib-resistant CLL, bearing a clone with BTK and PLCγ2 mutations, who responded immediately to single-agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with modulation of T and myeloid cells. Conclusions: Our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B-cell numbers and T and myeloid cell pro-leukemia functions and support the use of duvelisib as a valuable approach for therapeutic interventions, including for patients refractory to BTKi.

Effects of inhibition of PI3K isoforms on CLL-cell proliferation, survival, and migration.

Purpose:Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL.Experimental Design:Responses to PI3K-δi, PI3K-γi, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compartments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naïve and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib.Results:We demonstrate the essential roles of PI3K-δ for CLL B-cell survival and migration, of PI3K-γ for T-cell migration and macrophage polarization, and of dual inhibition of PI3K-δ,γ for efficacious reduction of leukemia burden. We also show that samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in a xenograft model, irrespective of BTK mutations. In support of this, we report a patient with ibrutinib-resistant CLL, bearing a clone with BTK and PLCγ2 mutations, who responded immediately to single-agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with modulation of T and myeloid cells.Conclusions:Our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B-cell numbers and T and myeloid cell pro-leukemia functions and support the use of duvelisib as a valuable approach for therapeutic interventions, including for patients refractory to BTKi.

IC50 values of PI3K isoform inhibitors used. Duvelisib5, IPI-3063 (PI3K-d inhibitor)5, IPI-549 (PI3K-g inhibitor used in vitro)50, IPI-5243 (PI3K-g inhibitor used in vivo).

Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). Efficacy and safety of acalabrutinib monotherapy were evaluated in a treatment-naive CLL cohort of a single-arm phase 1/2 trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patients had a median age of 64 years and 47% had Rai stage III/IV disease. Acalabrutinib was administered orally 200 mg once daily, or 100 mg twice daily until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene, and 12 (18%) had TP53 aberrations. After median follow-up of 53 months, 85 patients remain on treatment; 14 discontinued treatment, mostly because of adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Because of improved trough BTK occupancy with twice-daily dosing, all patients were transitioned to 100 mg twice daily. Median duration of response (DOR) was not reached; 48-month DOR rate was 97% (95% confidence interval, 90-99). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) because of second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). Durable efficacy and long-term safety of acalabrutinib in this trial support its use in clinical management of symptomatic, untreated patients with CLL.

Purpose Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in CLL. Umbralisib a novel, highly selective PI3Kδ/CK1e inhibitor, is active and well tolerated in CLL patients. This phase 2 trial evaluated umbralisib in CLL patients who are intolerant to prior BTK or PI3K inhibitor therapy. Patients and methods In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg oral daily in CLL patients requiring therapy per investigator discretion who were intolerant to prior BTK or PI3K inhibitor therapy, until progression or toxicity. Primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure and umbralisib safety profile. DNA isolated from buccal swabs was genotyped for polymorphisms in CYP3A4, CYP3A5 and CYP2D6. Results Fifty-one patients were enrolled (44 BTKi and 7 PI3Kδi intolerant). Median age was 70 years (range 48-96), median of 2 prior lines of therapy (1-7), 24% had del17p and/or TP53 mutation, and 65% were IGHV unmutated. Most common AEs leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median progression free survival (PFS) was 23.5 months (95% CI 13.1-not estimable). 58% of patients were on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib due to an AE. Eight patients (16%) had dose reductions and were successfully re-challenged. Conclusions Umbralisib is safe and effective in this BTK and alternate PI3K inhibitor intolerant CLL population. These are the first prospective data to confirm that switching from a BTK or alternate PI3K inhibitor to umbralisib can result in durable, well tolerated responses.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

The development of highly effective targeted therapies has led to a new treatment paradigm in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). Despite these advances, many patients will eventually require alternative treatment strategies due to the emergence of tolerability issues or resistance to these novel agents. Duvelisib is a first-in-class, potent oral agent with dual inhibitor activity against the δ and γ isoforms of phosphoinositide 3-kinase (PI3Kδ and PI3Kγ), which are specific to the hematopoietic system. Dysregulation of the PI3K/PTEN/AKT/mTOR pathway has been implicated in cancer cell growth, survival and metabolism and has been the subject of cancer drug development in recent years. Duvelisib demonstrated activity in CLL/SLL in early trials, leading to further evaluation in the Phase 3 DUO trial that compared duvelisib against ofatumumab in patients with relapsed/refractory CLL/SLL. This trial led to the Food and Drug Administration (FDA) approval for the treatment of adult patients with CLL/SLL after at least two prior lines of therapy. The major reason for therapy discontinuation is the development of serious adverse events, which include severe infections and diarrhea/colitis, precluding its widespread use. Ongoing clinical trials are evaluating duvelisib in combination strategies and with alternate dosing schedules in patients with CLL/SLL. With close monitoring, duvelisib can be a promising drug for the treatment of patients with relapsed or refractory CLL/SLL. This review summarizes the relevant clinical data from recent clinical advances in CLL and aims to interpret the duvelisib trials while exploring strategies to improve its use and adverse event management in the era of novel targeted agents.

Duvelisib (IPI-145), a first-in-class, oral, dual PI3K-δ,γ inhibitor, has been approved by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL), small lymphocytic and follicular lymphoma. Duvelisib potently inhibits PI3K-δ and PI3K-γ, thereby offering a novel therapeutic approach. Here we aimed to understand how duvelisib targets CLL cells and the tumor microenvironment (TME) and hence how it affects CLL, even with BTK-resistant disease. We first assessed the distinct contributions of PI3K-δ and PI3K-γ on CLL cell survival, proliferation, and migration in vitro by using PI3K-δ (PI3K-δi) or PI3K-γ (PI3K-γi) specific inhibitors in addition to duvelisib. We found a significant reduction in viable CLL cells after exposure to PI3K-δi and duvelisib. By measuring Ki67 and p-AKT levels, we found duvelisib and PI3K-δi more potently block CLL cell proliferation than PI3K-γi. PI3K-δi and duvelisib also significantly reduced the migration of CLL B cells into the spleen relative to control. In contrast, PI3K-γi inhibited T cell not B cell homing in vitro and in vivo. We then investigated the impact of single versus dual inhibitory agents on myeloid cells. Tumor-associated macrophages (TAMs) of the “M2 phenotype” contribute to a pro-tumor TME by preventing the induction of T cell mediated anti-tumor immunity. We expanded murine bone marrow derived monocytes and then polarized them to M2 macrophages, in the absence or presence of PI3Ki. At 100nM, PI3K-γi, but not PI3K-δi, significantly inhibited M2 polarization. Duvelisib significantly reduced Arg1 expression at doses equal to or above 10nM. While co-culturing leukemic B cells with M2-polarized murine macrophages increased CLL-cell survival, addition of duvelisib to such co-cultures significantly reduced CLL cell survival. Altogether, duvelisib sensitizes primary CLL cells to apoptosis and abrogates M2 cell-mediated CLL-cell survival. Finally, in a patient-derived xenograft mouse model (PDX), we demonstrated the essential roles of PI3K-δ and PI3K-γ in the CLL TME. Specifically, we found a more efficacious inhibition in CLL cell burden by dual inhibition of PI3K-δ,γ. Also, samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in PDX, irrespective of BTK mutations. In support of this, we identified an ibrutinib resistant CLL patient, with a clone exhibiting BTK and PLCγ2 mutations who responded immediately to single agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with subsequent modulation of T and myeloid cells. In conclusion, our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B cell numbers and T and myeloid cell pro-leukemia functions, supporting the use of duvelisib as a potentially valuable therapeutic intervention, including for patients refractory to BTKi. Citation Format: Shih-Shih Chen, Jacqueline C. Barrientos, Gerardo Ferrer, Priyadarshini Ravichandran, Michael Ibrahim, Yasmine Kieso, Jeffery L. Kutok, Marisa Peluso, Sujata Sharma, David T. Weaver, Jonathan A. Pachter, Kanti R. Rai, Nicholas Chiorazzi. Duvelisib eliminates CLL B Cells, impairs CLL-supporting cells, and overcomes ibrutinib resistance in a patient-derived xenograft model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4933.

A diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) was elicited during acute COVID‐19 infection. COVID‐19 spike proteins trigger the alternative pathway of complement. Acute SARS‐CoV‐2 infection possibly expanded an existing PIG‐A mutation.

BACKGROUND: Treatment of chronic lymphocytic leukemia (CLL) with a fixed-duration venetoclax (Ven)-based regimen is now a standard of care (SOC) option for both frontline and relapsed refractory (R/R) disease based on results of the CLL14 and MURANO trials (Fischer et al NEJM 2019, Seymour et al NEJM 2018). As fixed-duration Ven regimens are now a SOC, it is expected that an increasing number of patients (pts) will ultimately progress after Ven exposure and require additional CLL-directed therapy. While many discuss re-treatment with Ven as a subsequent treatment option, the current literature contains response data on an extremely limited number of evaluable pts (11 pts MURANO, overall response rate (ORR) 55%; 3 pts VEN 365, ORR 100%). Whether re-treatment with Ven is an acceptable option remains an important unanswered clinical question. METHODS: We conducted a multicenter, retrospective study of CLL pts treated with a Ven-based regimen (Ven1) and then re-treated with a second Ven-based regimen (Ven2) in a later line of therapy (LOT). Data were collected from 13 centers and the CLL Collaborative Study of Real-World Evidence database. CLL pts were eligible for inclusion if they were treated with a Ven-based regimen in any LOT and then re-treated with a Ven-based regimen as a later LOT. Collected data included demographics, prognostic disease characteristics, tumor lysis syndrome (TLS) risk and incidence, clinical response and reasons for treatment discontinuation (dc). The primary study endpoint was investigator-assessed ORR (CR: complete response, PR: partial response, SD: stable disease, PD: progression of disease, iwCLL 2018). Kaplan-Meier method was used to estimate progression free survival (PFS). All other analyses were descriptive. RESULTS: We identified 25 pts who were re-treated with Ven. Pt characteristics prior to treatment with Ven1 are summarized in Table 1. In 24% of pts (n=6), Ven1 was administered as part of a clinical trial. Median prior LOT was 2 (range 0-10) with 12.0% treatment naïve and 60% with prior BTKi exposure. The majority of pts had ≥1 high-risk prognostic marker: del17p (39%), TP53 mut (27%), complex karyotype ≥5 abnormalities (30%) and unmutated IGHV (84%). For Ven1, treatment regimens, TLS risk, and dose are summarized in Table 2. With a median duration of exposure of 15 months (mos) (64% pts > 12 mos) for Ven1, the ORR was 88% (CR: 48%, PR: 40%, Figure 1A). Ten pts had minimal residual disease (MRD) assessments by flow cytometry; 8 pts (80%) achieved undetectable MRD (10^-4). Most common reasons for Ven1 dc included: toxicity (28%), completion of planned therapy (24%), MD/pt preference (24%), other (12%), alloHSCT (4%) and cost (4%). There was a median of 8.7 mos (36% > 12 mos) between Ven1 and the initiation of Ven2, and 88% did not receive another LOT between Ven1 and Ven2. Reasons for Ven2 initiation were either CLL progression (87.5%) or MRD-positive relapse (12.5%). For Ven2, TLS risk, TLS incidence and dose information are outlined in Table 2. TLS was a rare event during Ven re-treatment (4.5%, lab only). For Ven2, Ven monotherapy was the most common regimen (52%). Standard Ven dose-escalation was used for re-initiation in 17 of 19 pts with available data, however 1 pt started Ven2 at 400 mg daily (no TLS) and another underwent a prolonged ramp-up period. At the time of this analysis, 18 pts had available response assessments for Ven2: ORR is 72.2% (CR: 4, PR: 9, SD: 4 and PD: 1, Figure 1B). Median time from Ven2 to progression or last follow up is 8 mos (0.2-29 mos). Median PFS has not been reached. Estimated 12-month PFS is 69.1%. For pts with a CR to Ven2, median follow up time is 14.5 mos vs 7 mos for pts with PR or SD. Of 25 pts re-treated with Ven, 68% remain on Ven2 presently and 32% have discontinued Ven2, including due to CLL progression (n=4), completion of planned therapy (n=1), unrelated death (n=1), MD/pt preference (n=1). CONCLUSIONS: To our knowledge, this is the largest reported cohort of CLL pts re-treated with Ven after a prior Ven-based regimen. The high ORR in this pt population (median 2 prior therapies) suggests that re-treatment is a promising strategy and should be considered in treatment sequencing algorithms. Notably, pts with a CR to Ven2 had a longer median follow up than those with a PR or SD, suggesting a likelihood of deeper responses with time. Given the promising ORR, further research to prospectively validate Ven re-treatment is warranted. Updated data will be presented. Disclosures Allan: Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzoor:Abbvie: Current Employment, Other: may hold stock or stock options. Pu:Takeda Pharmaceuticals: Consultancy. Barr:Gilead: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Morphosys: Consultancy; TG therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy. Coombs:LOXO Oncology: Honoraria; MEI Pharma: Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding. Skarbnik:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rhodes:Verastem: Consultancy; Abbvie/Genentech: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy. Barrientos:Janssen: Honoraria; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding; Bayer: Consultancy; Genentech: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy. Roeker:American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Leslie:Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kamdar:Roche: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Simkovic:Abbvie: Consultancy, Other: travel expenses. Lansigan:Seattle Genetics: Consultancy; BMS: Consultancy; BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding. Zelenetz:Novartis: Consultancy; Gilead: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Roche: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; MorphoSys: Research Funding; Amgen: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding. Moskowitz:Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Merck: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Seattle Genetics: Consultancy. Goy:Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Infinity Verastem: Research Funding; Infinity: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; CALBG: Research Funding; Constellation: Research Funding; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Xcenda: Consultancy; Hackensack UMC and University of Nebraska: Research Funding. Feldman:Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Trillium: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Furman:Verastem: Consultancy; Genentech: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy; Pharmacyclics: Consultancy; Oncotarget: Consultancy; Loxo Oncology: Consultancy; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy. Mato:Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Adaptive: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

PURPOSE A randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies. PATIENTS AND METHODS Patients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety. RESULTS The long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases. CONCLUSION IDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.

Clonal expansion of B cell chronic lymphocytic leukemia (B-CLL) occurs within lymphoid tissue pseudofollicles. IL-15, a stromal cell–associated cytokine found within spleens and lymph nodes of B-CLL patients, significantly boosts in vitro cycling of blood-derived B-CLL cells following CpG DNA priming. Both IL-15 and CpG DNA are elevated in microbe-draining lymphatic tissues, and unraveling the basis for IL-15–driven B-CLL growth could illuminate new therapeutic targets. Using CpG DNA-primed human B-CLL clones and approaches involving both immunofluorescent staining and pharmacologic inhibitors, we show that both PI3K/AKT and JAK/STAT5 pathways are activated and functionally important for IL-15→CD122/ɣc signaling in ODN-primed cells expressing activated pSTAT3. Furthermore, STAT5 activity must be sustained for continued cycling of CFSE-labeled B-CLL cells. Quantitative RT-PCR experiments with inhibitors of PI3K and STAT5 show that both contribute to IL-15–driven upregulation of mRNA for cyclin D2 and suppression of mRNA for DNA damage response mediators ATM, 53BP1, and MDC1. Furthermore, protein levels of these DNA damage response molecules are reduced by IL-15, as indicated by Western blotting and immunofluorescent staining. Bioinformatics analysis of ENCODE chromatin immunoprecipitation sequencing data from cell lines provides insight into possible mechanisms for STAT5-mediated repression. Finally, pharmacologic inhibitors of JAKs and STAT5 significantly curtailed B-CLL cycling when added either early or late in a growth response. We discuss how the IL-15–induced changes in gene expression lead to rapid cycling and possibly enhanced mutagenesis. STAT5 inhibitors might be an effective modality for blocking B-CLL growth in patients.

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with

Cancer pathogenesis involves the interplay of tumor- and microenvironment-derived stimuli. Here we focused on the influence of an immunomodulatory cell type, myeloid-derived suppressor cells (MDSCs), and their lineage-related subtypes on autologous T lymphocytes. Although MDSCs as a group correlated with an immunosuppressive Th repertoire and worse clinical course, MDSC subtypes (polymorphonuclear, PMN-MDSC, and monocytic, M-MDSCs) were often functionally discordant. In vivo, PMN-MDSCs existed in higher numbers, correlated with different Th-subsets, and more strongly associated with poor clinical course than M-MDSCs. In vitro, PMN-MDSCs were more efficient at blocking T-cell growth and promoted Th17 differentiation. Conversely, in vitro M-MDSCs varied in their ability to suppress T-cell proliferation, due to the action of TNFα, and promoted a more immunostimulatory Th compartment. Ibrutinib therapy impacted MDSCs differentially as well, since after initiating therapy, PMN-MDSC numbers progressively declined, whereas M-MDSC numbers were unaffected, leading to a set of less immunosuppressive Th cells. Consistent with this, clinical improvement based on decreasing CLL-cell numbers correlated with the decrease in PMN-MDSCs. Collectively, the data support a balance between PMN-MDSC and M-MDSC numbers and function influencing CLL disease course.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (

The advent of novel B-cell receptor pathway targeting agents like ibrutinib dramatically changed management of B-cell malignancies. However, with concomitant anticoagulation (AC) and antiplatelet (AP) therapy, ibrutinib is associated with increased bleeding. This post hoc analysis aimed to determine the role of AC/AP therapy in patients with idelalisib-treated B-cell malignancies and to establish if it contributes to increased bleeding events. Data from two idelalisib trials (rituximab ± idelalisib in chronic lymphocytic leukemia [CLL] and idelalisib monotherapy in indolent non-Hodgkin lymphoma [iNHL]) were analyzed. Antithrombotic therapy was common (36%-63%), with comparable bleeding incidence across treatment groups (14%-19%; p = 0.56). Bleeding events of grade ≥3 occurred in 0.9% and 3.2% of the idelalisib-treated CLL and iNHL cohorts, respectively. Our findings demonstrate no increase in bleeding events with simultaneous AC/AP treatment and idelalisib use. Hemorrhagic risk is prevalent in these patients and an important consideration when evaluating available treatment options. ClinicalTrials.gov identifiers: NCT01539512 and NCT01282424.

The treatment of chronic lymphocytic leukemia (CLL) embodies one of the great success stories in translational research, with the development of therapies aimed at disrupting crucial pathways that allow for the survival and proliferation of the malignant clone. The arrival of targeted agents into our armamentarium, along with the advent of novel monoclonal antibodies that can achieve deeper remissions, has steered the field to a new treatment paradigm. Given the panoply of therapeutic options available, the question arises whether chemotherapy still has a role in the management of CLL. The novel targeted agents, which include the Bruton’s tyrosine kinase inhibitors, ibrutinib and acalabrutinib, along with the B-cell lymphoma-2 inhibitor, venetoclax, are highly effective in achieving a response with improved remission duration and survival, particularly in high-risk patients. Despite this major progress, the new agents bring a unique set of toxicities unlike those associated with cytotoxic chemotherapy. There is a paucity of head-to-head comparisons among all of the novel agents, because their approval was based on randomization against traditional chemoimmunotherapeutic regimens. Parallel to the increase in the number of available targeted agents, there has been a significant improvement in quality of life and life expectancy of the patients with a CLL diagnosis over the last decade. Our review will examine whether “chemotherapy-free” frontline treatment approaches are worth the associated risks. Our goal is to help identify optimal treatment strategies tailored to the individual by reviewing available data on monotherapy vs combination strategies, depth of response, treatment duration, and potential toxicities.

Patient-derived xenograft models of chronic lymphocytic leukemia (CLL) can be created using highly immunodeficient animals, allowing analysis of primary tumor cells in an in vivo setting. However, unlike many other tumors, CLL B lymphocytes do not reproducibly grow in xenografts without manipulation, proliferating only when there is concomitant expansion of T cells. Here we show that in vitro pre-activation of CLL-derived T lymphocytes allows for a reliable and robust system for primary CLL cell growth within a fully autologous system that uses small numbers of cells and does not require pre-conditioning. In this system, growth of normal T and leukemic B cells follows four distinct temporal phases, each with characteristic blood and tissue findings. Phase 1 constitutes a period during which resting CLL B cells predominate, with cells aggregating at perivascular areas most often in the spleen. In Phase 2, T cells expand and provide T-cell help to promote B-cell division and expansion. Growth of CLL B and T cells persists in Phase 3, although some leukemic B cells undergo differentiation to more mature B-lineage cells (plasmablasts and plasma cells). By Phase 4, CLL B cells are for the most part lost with only T cells remaining. The required B-T cell interactions are not dependent on other human hematopoietic cells nor on murine macrophages or follicular dendritic cells, which appear to be relatively excluded from the perivascular lymphoid aggregates. Notably, the growth kinetics and degree of anatomic localization of CLL B and T cells is significantly influenced by intravenous versus intraperitoneal administration. Importantly, B cells delivered intraperitoneally either remain within the peritoneal cavity in a quiescent state, despite the presence of dividing T cells, or migrate to lymphoid tissues where they actively divide; this dichotomy mimics the human condition in that cells in primary lymphoid tissues and the blood are predominately resting, whereas those in secondary lymphoid tissues proliferate. Finally, the utility of this approach is illustrated by documenting the effects of a bispecific antibody reactive with B and T cells. Collectively, this model represents a powerful tool to evaluate CLL biology and novel therapeutics in vivo.

The development of vaccinations has been instrumental in the ongoing effort to combat the COVID-19 pandemic. Although the benefits of vaccination are unquestionable, there have been reports of potentially rare life-threatening complications following vaccination including thrombocytopaenia, haemolytic anaemia, vasculitis and myocarditis. Haemophagocytic lymphohistiocytosis (HLH), a rare but life-threatening inflammatory condition, has also been described postadenoviral vector COVID-19 vaccination but it has never been reported post-messenger RNA (mRNA) COVID-19 vaccination. We report two cases of HLH admitted to our hospital after administration of COVID-19 mRNA vaccines. We also searched the vaccine adverse event reporting system and found 50 reports of suspected HLH following COVID-19 vaccination. Presently, we cannot define a causality between COVID-19 mRNA vaccination and HLH development. However, we hope the reporting of our two cases (and additional cases seen in the adverse event reporting database) will help us determine whether there is a potential relationship. Prompt recognition of this condition is of utmost importance to initiate life-saving therapy.