Chronic Lymphocytic Lymphoma Research Articles

Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab

Objective Zanubrutinib is a highly selective, next-generation Bruton’s tyrosine kinase inhibitor. In the phase 3 SEQUOIA trial (NCT03336333), treatment with zanubrutinib resulted in significantly improved progression-free survival compared to bendamustine plus rituximab (BR) in adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) without del(17p). The current analysis compared the effects of zanubrutinib versus BR on patients’ health-related quality-of-life (HRQoL). Methods In the SEQUOIA trial, patient-reported outcomes (PROs) were assessed at baseline and every 12 weeks (3 cycles) using the EORTC QLQ-C30 and EQ-5D-5L. Descriptive analyses were performed on all the questionnaires’ scales and a mixed model for repeated measures was performed using the key QLQ-C30 endpoints of global health status/QoL (GHS/QoL), physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting at weeks 12 and 24. Results Compared with BR-treated patients, those in the zanubrutinib arm experienced greater improvements in HRQoL outcomes at both weeks 12 and 24. By week 24, mean change differences (95% confidence interval) between the arms were significant for GHS/QoL (4.9 [0.9, 9.0]), physical functioning (3.8 [0.8, 6.7]), diarrhea (−6.2 [−10.0, −2.5]), fatigue (−4.5 [−8.9, −0.1]), and nausea/vomiting (−4.5 [−8.9, −0.1]); role functioning (4.8 [−0.2, 9.7]) was marginally better in the zanubrutinib arm and there were no differences in pain symptoms (−0.4 [−4.3, 5.1]) between the arms. Conclusions During the first 24 weeks of treatment, zanubrutinib was associated with better HRQoL outcomes in patients with treatment-naive CLL/SLL without del(17p) compared to BR. Trial registration The SEQUOIA trial is registered on clinicaltrials.gov as SEQUOIA trial (NCT03336333).

Current Approach in the Management of Secondary Immunodeficiency in Patients with Hematological Malignancies: Spanish Expert Consensus Recommendations.

A Delphi-based survey was designed to assess the opinions of clinical hematologists (n = 17) and clinical immunologists (n = 18) from across Spain on secondary immunodeficiencies (SID) in the management of oncohematological patients. There was 100% agreement on the need to have available guidelines for the management of immunodeficiency in hematological patients; to perform a baseline immunological evaluation in patients with chronic lymphocytic leukemia (CLL), multiple myeloma (MM), lymphoma and hematopoietic stem cell transplantation (HSCT) recipients; and to quantify serum IgG, IgA and IgM levels when SID is suspected. More than 90% agreed on the need for active immunization against seasonal influenza and H1N1, pneumococcus and Haemophilus influenzae. There was a consensus on the monitoring of IgG levels every 3 months (83%) and the need to have available a clinical protocol for the use of IVIG in the management of SID (94%), to monitor trough IgG levels to determine the correct IVIG dose (86%) and to discontinue IVIG after the recovery of IgG levels after 12 months of follow-up (77%). The findings of the present survey may be useful recommendations for hematologists and immunologists to improve the management of SID in daily practice.

Association between cumulative airborne dioxin exposure and non-Hodgkin's lymphoma risk in a nested case-control study within the French E3N cohort

BackgroundDioxins are a family of chemical molecules that are chlorinated, lipophilic, and bio-accumulative. They are thought to enhance the risk of non-lymphoma Hodgkin's due to their known carcinogenic properties (NHL). This is the first epidemiological research to investigate the relationship between repeated emissions of airborne dioxin exposure and the risk of NHL. ObjectiveA case-control study nested within the French E3N cohort of 98,995 women covered by the health insurance provider of the national education system evaluated the association between cumulative airborne dioxin exposure and NHL risk. Materials and methodsNHL incident cases (368) and controls (368) were compared. Over the duration of the study, participants' residential histories and the locations of industrial sites were gathered (1990–2008). Using a Geographic Information System (GIS)-based exposure index, the cumulative exposure to airborne dioxins for each participant was calculated at the individual address level. The odds ratios (OR) and 95 % confidence intervals (CI) were calculated using multivariable conditional logistic regression models (CI). ResultsThe log-transformed continuous cumulative dioxin exposure index was substantially correlated with the risk of NHL (OR1.2 (95 % CI 1.0,1.4) for an increase in log-TEQ/m2 of 4.4, or one standard deviation). The combined chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) subtype was significantly associated with NHL histological subtypes (OR 1.6 (95 % CI 1.1,2.3)). ConclusionThe findings of this study demonstrate a significant positive correlation between cumulative airborne dioxin exposure and the risk of NHL in women, and more specifically, a significant positive association for the CLL & SLL subtype. These results help to support the attempts to reduce the exposure to dioxins in the air.

Cancer-associated fibroblasts in hematologic malignancies: elucidating roles and spotlighting therapeutic targets.

Hematologic malignancies comprise a diverse range of blood, bone marrow, and organ-related disorders that present significant challenges due to drug resistance, relapse, and treatment failure. Cancer-associated fibroblasts (CAFs) represent a critical component of the tumor microenvironment (TME) and have recently emerged as potential therapeutic targets. In this comprehensive review, we summarize the latest findings on the roles of CAFs in various hematologic malignancies, including acute leukemia, multiple myeloma, chronic lymphocytic leukemia, myeloproliferative neoplasms, and lymphoma. We also explore their involvement in tumor progression, drug resistance, and the various signaling pathways implicated in their activation and function. While the underlying mechanisms and the existence of multiple CAF subtypes pose challenges, targeting CAFs and their associated pathways offers a promising avenue for the development of innovative treatments to improve patient outcomes in hematologic malignancies.

CLL-587 Real-World Treatment Outcomes in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Who Were Treated With First-Line Single-Agent Ibrutinib vs Chemoimmunotherapy

CLL-587 Real-World Treatment Outcomes in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Who Were Treated With First-Line Single-Agent Ibrutinib vs Chemoimmunotherapy

POSTER: CLL-587 Real-World Treatment Outcomes in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Who Were Treated With First-Line Single-Agent Ibrutinib vs Chemoimmunotherapy

POSTER: CLL-587 Real-World Treatment Outcomes in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Who Were Treated With First-Line Single-Agent Ibrutinib vs Chemoimmunotherapy

Chronic Lymphocytic Lymphoma / Leukemia Infiltration of Prostate Gland Presenting with Hematuria: A Case Report

Chronic Lymphocytic Lymphoma / Leukemia Infiltration of Prostate Gland Presenting with Hematuria: A Case Report

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia

BackgroundPatients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton’s tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition.MethodsWe conducted a phase 1–2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety.ResultsA total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event.ConclusionsIn this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.)

Impacts of early therapy response, interval to therapy interruption, and cumulative therapy interruption duration on outcome of ibrutinib therapy in relapsed/refractory chronic lymphocytic leukemia.

To investigate the impact of early response and treatment interruption on the survival of patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (r/r CLL/SLL) treated with ibrutinib.This post hoc analysis used data of patients received ibrutinib treatment from an open-label, multicenter phase 3 study comparing ibrutinib with rituximab in patients with r/r CLL/SLL. The association of complete or partial response at 6months, interruption within the first 6months, cumulative interruption durations during the ibrutinib-treated period with progression-free survival (PFS) and overall survival (OS) were evaluated using the adjusted Cox hazard proportional model.The study included 87 patients treated with ibrutinib, of which 74 patients had at least 6months of ibrutinib treatment and were analyzed. The response at 6months did not affect PFS (HR = 0.58, 95%CI: 0.22-1.49) or OS (HR = 0.86, 95%CI: 0.22-3.31). The onset of interruption before or after 6months was not associated with PFS (HR = 0.88, 95%CI: 0.34-2.30) or OS (HR = 0.75, 95%CI: 0.23-2.52). However, a cumulative interruption of more than 35days was independently associated with worse PFS (HR = 2.4, 95%CI: 0.99-5.74) and OS (HR = 2.6, 95%CI: 0.88-7.44). Continuous interruption for more than 14days was associated with a numerically lower 3-year PFS rate (> 14 vs. ≤ 14days: 42% vs. 73%) and 3-year OS rate (> 14 vs. ≤ 14days: 58% vs. 84%, both P > 0.05).Response status at 6months or early therapy interruptions did not affect survival in patients with r/r CLL/SLL treated with ibrutinib. However, a cumulative temporary interruption of more than 35days could potentially impact patient outcomes.

Ibrutinib induced sensorimotor neuropathy: A novel side effect

Chemotherapy-induced peripheral neuropathy (CIPN) is a well-documented toxicity leading to dose limitation.Ibrutinib is an oral Bruton’s Tyrosine Kinase (BTK) inhibitor approved for treating chronic lymphocytic lymphoma. The most common neurological side effects of Ibrutinib include headache and dizziness. Herein, we report peripheral neuropathy as a dose-limiting manifestation of Ibrutinib treatment.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1–2 study

Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. Juno Therapeutics, a Bristol-Myers Squibb Company.

Real-world treatment outcomes in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who were treated with first-line single-agent ibrutinib vs. chemoimmunotherapy.

e19509 Background: Real-world evidence on Bruton Tyrosine Kinase Inhibitor treatment vs chemoimmunotherapy (CIT) for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) has been limited to certain practice settings; research using a large and more comprehensive data source is warranted. Methods: This retrospective cohort study evaluated treatment outcomes among patients with CLL/SLL treated with first-line (1L) ibrutinib (IBR) or CIT using the US claims data from the Komodo Health payer-complete dataset, derived from >150 private insurers and >140 million insured individuals from 2015 to 2022. This study included adult patients with CLL/SLL who initiated 1L single-agent IBR or CIT (defined as no prior CLL/SLL treatment for ≥12 months in the baseline period) on or after March 2016. Time to next treatment (TTNT) was defined as the time from initiation (index date) of 1L treatment to treatment add-on or switch to a next line of therapy ≥29 days post-index and was compared using Cox proportional hazards models. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Results: A total of 3570 1L IBR- and 2391 CIT-treated patients were included, with the mean age 68 vs 64 years, 63% vs 66% male, and mean Quan-Charlson Comorbidity Index score 2.87 vs 3.05, respectively. Median follow-up was 26 vs 31 months, and 13% vs 26% of patients recorded a next treatment during the study period for IBR and CIT, respectively. At 1-, 3-, and 5-year post-index, the probabilities (95% confidence interval [CI]) of not initiating a new treatment were 92% (91%-93%), 83% (81%-84%) and 76% (73%-78%) vs 88% (87%-89%), 70% (68%-73%) and 56% (53%-60%) for the IBR and CIT cohorts, respectively. After controlling for baseline characteristics, 1L IBR patients were significantly less likely to initiate the next line of therapy during the study period (hazard ratio 0.61, 95% CI 0.54-0.69, p<0.001). Conclusions: 1L single-agent IBR was associated with a significantly lower risk of advancing to next line of treatment compared to CIT in this large claims-based data set, reinforcing real-world effectiveness of 1L IBR for CLL in an insured US patient population. [Table: see text]

Chronic lymphocytic leukemia/small lymphocytic lymphoma nationwide analysis: Comparing sociodemographic and survival outcomes among Hispanics and non-Hispanics in the United States.

e19505 Background: In essence, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are the same , CLL being the most common leukemia in Western countries. (Blood PMID 29540348, CA Cancer J Clin PMID 35020204) Survival outcomes in CLL/SLL among Hispanics (HI) and Non-Hispanics (NH) have been controversial. (Cancer Causes Control PMID 34677741, Cold Spring Harb Mol Case Stud PMID 33593728) This analysis attempts to clarify if sociodemographic characteristics influence survival of HI diagnosed with CLL/SLL in the United States (US). Methods: Retrospective data analysis on CLL/SLL patients in the US reported to the Surveillance, Epidemiology, and End Results (SEER) 18 database from 2000-2018. Demographics, disease characteristics, and survival patterns were analyzed across ethnic groups, HI vs NH. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS). Multivariate analysis and propensity score matching was performed, adjusting for age, stage, and B-symptoms. Results: 98884 CLL/SLL patients were included, 5012 HI. Males predominated in both HI and NH. HI compared to NH, were diagnosed at a younger median age, 68 years vs 70 years, respectively [p<0.001]. Majority of patients belonged to the age bracket of 60-80 years; favoring a younger age distribution in HI. Most patients were white, and NH had greater heterogeneity [p<0.001]. Unknown stage at diagnosis followed by advance stage (III/IV) prevailed for both ethnicities [p=0.075]. B-symptoms were mostly unknown in both groups. The tendency was towards not receiving radiation as part of the treatment. Survival probability at 2, 5 and 10 years for HI (0.829, 0.677, and 0.474) was similar compared to NH (0.831, 0.664 and 0.437), respectively. The median survival time was 9.3 years for HI vs 8.5 years for NH, with a statistically significant difference in OS favoring HI [p=0.0045] On multivariate analysis, patients older than 80 years and between 60-80, had worse OS than those less than 60, with hazard ratio (HR) 7.5 [95% CI: 7 – 8.1] and 2.5 [95% CI: 2.4-2.7], respectively. Also, stage III and IV, had inferior OS than those at early stages, with HR 1.4 [95% CI: 1.1 – 1.6] and HR 1.2 [95% CI: 1 – 1.4], respectively. Conclusions: In this analysis, HI with CLL/SLL have a superior OS, which was noted to be statistically significant. Also, multivariate analysis showed correlation of better OS when CLL/SLL was identified at a younger age and early stages. Although demographic differences may be driving the survival effect in HI as they were noted to be younger; identification and better understanding of intrinsic disease characteristics, treatment patterns, and biological variables; may aid in the understanding on how these factors contribute and impact the survival advantage in this ethnic group.

REAL‐WORLD DURATION OF VENETOCLAX TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA AND SMALL LYMPHOCYTIC LYMPHOMA

Introduction: Venetoclax (V) is an approved fixed-duration treatment (tx) for chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL), as a 12-cycle regimen (∼12 mos) with obinutuzumab (O) in the first-line (1L) setting or as a 24-cycle regimen (∼24 mos) with rituximab (R) in the relapsed/refractory (R/R) setting. We analyzed real-world tx patterns of V+O in 1L and V+R in R/R settings in patients (pts) with CLL/SLL in the United States. Methods: A retrospective cohort analysis was conducted using the IQVIA PharMetrics® Plus database to identify pts ≥18 y treated with V+O (1L cohort; May 2019 to September 2021) or V+R (R/R cohort; June 2018 to September 2021). Start of tx regimen was defined as the index date. All pts were required to have ≥1 diagnosis code for CLL/SLL and continuous enrollment 12 mos prior to and ≥3 mos after index date. Duration of tx (DoT) was defined as time from index date to earliest of either tx discontinuation (i.e., ≥60-d gap in V prescription refills) or censoring (i.e., end of follow-up). Fixed-duration tx cycle was defined as 12- or 24-cycle dosing (days 336−364 for 1L setting and days 707−735 for R/R setting, based on the dosing schedule plus 28 days). Kaplan-Meier analysis was used to estimate the probability of remaining on tx for the 1L and R/R cohorts. Results: A total of 116 pts in 1L setting (mean age, 62.3 y) and 145 pts in R/R setting (mean age, 64.2 y) were identified; 48.3% of R/R pts had prior targeted therapy. Median (95% CI) DoT in V+O pts (n = 115) was 12.4 (11.5, 13.4) mos over a median follow-up of 11.4 mos; probability of remaining on tx at 12, 18, and 24 mos was 56.4%, 20.2%, and 5.1%. Median (95% CI) DoT in V+R pts (n = 133) was 24.5 (13.4, 25.2) mos over a median follow-up of 15.5 mos; probability of remaining on tx at 24, 30, and 36 mos was 53.8%, 19.0%, and 19.0%. Among V+O pts, 47.8% (55/115) had ≥12 mos follow-up, of whom 9.1% had fixed cycles and 38.2% discontinued early (median DoT: 4.6 mos). Among V+R pts, 29.3% (39/133) had ≥24 mos follow-up, of whom 5.1% had fixed cycles and 46.2% discontinued early (median DoT: 7.1 mos). The remaining pts in each cohort had DoT >12 or 24 cycles (Table). Conclusions: While median DoT was approximately 12 mos for V+O-treated pts (1L setting) and 24 mos for V+R-treated pts (R/R setting), a high number of pts did not maintain the fixed-dosing schedule. This study provides evidence that a V-based approach may not be suitable for all pts with CLL/SLL. Encore Abstract—previously submitted to regional or national meetings (up to <1’000 attendees), EHA 2023 The research was funded by: AstraZeneca Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract A. Teschemaker Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca S. Hakre Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Tse Research funding: AstraZeneca Pharmaceuticals. IQVIA received research funding from AstraZeneca to conduct this study. N. F. Shaikh Research funding: AstraZeneca Pharmaceuticals. IQVIA received research funding from AstraZeneca to conduct this study. Y. Gu Research funding: AstraZeneca Pharmaceuticals. IQVIA received research funding from AstraZeneca to conduct this study. A. Near Research funding: AstraZeneca Pharmaceuticals. IQVIA received research funding from AstraZeneca to conduct this study.

Health‐related quality of life in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma treated with liso‐cel in TRANSCEND CLL 004

Health‐related quality of life in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma treated with liso‐cel in TRANSCEND CLL 004

Humoral and cellular immune responses after three or four doses of BNT162b2 in patients with hematological malignancies.

Initial responses to coronavirus disease 2019 vaccination are impaired in patients with hematological malignancies. We investigated immune responses after three or four doses of BNT162b2 in patients with myeloid and lymphoid malignancies compared to controls, and identified risk factors for humoral and cellular nonresponse 1 year after first vaccination. In 407 hematological patients (45 myeloid, 362 lymphoid) and 98 matched controls, we measured immunoglobulin G (IgG) and neutralizing antibodies specific for the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline, 3 weeks, 2, 6, and 12 months, and interferon-γ release at 12 months. In patients with lymphoid malignancies, SARS-CoV-2 receptor-binding domain IgG concentration and mean neutralizing capacity was lower than in controls at all time points. A diagnosis of chronic lymphocytic B-cell leukemia (CLL) or lymphoma was associated with humoral nonresponse at 12 months compared to having multiple myeloma/amyloidosis (p < .001 and p = .013). Compared to controls, patients with lymphoid malignancies had increased risk of cellular nonresponse. A lymphoma diagnosis was associated with lower risk of cellular nonresponse compared to patients with multiple myeloma/amyloidosis, while patients with CLL had comparable response rates to patients with multiple myeloma/amyloidosis (p = .037 and p = .280). In conclusion, long-term humoral and cellular immune responses to BNT162b2 were impaired in patients with lymphoid malignancies.

In vivo activity of the dual PI3Kδ and PI3Kγ inhibitor duvelisib against pediatric acute lymphoblastic leukemia xenografts.

Acute lymphoblastic leukemia (ALL) remains one of the most common causes of cancer-related mortality in children. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases, and aberrations in the PI3K pathway are associated with several hematological malignancies, including ALL. Duvelisib (Copiktra) is an orally available, small molecule dual inhibitor of PI3Kδ and PI3Kγ, that is Food and Drug Administration (FDA) approved for the treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Here, we report the efficacy of duvelisib against a panel of pediatric ALL patient-derived xenografts (PDXs). Thirty PDXs were selected for a single mouse trial based on PI3Kδ (PIK3CD) and PI3Kγ (PIK3CG) expression and mutational status. PDXs were grown orthotopically in NSG (NOD.Cg-Prkdcscid IL2rgtm1Wjl /SzJAusb) mice, and engraftment was evaluated by enumerating the proportion of human versus mouse CD45+ cells (%huCD45+ ) in the peripheral blood. Treatment commenced when the %huCD45+ reached greater than or equal to 1%, and events were predefined as %huCD45+ greater than or equal to 25% or leukemia-related morbidity. Duvelisib was administered per oral (50mg/kg, twice daily for 28days). Drug efficacy was assessed by event-free survival and stringent objective response measures. PI3Kδ and PI3Kγ mRNA expression was significantly higher in B-lineage than T-lineage ALL PDXs (p-values <.0001). Duvelisib was well-tolerated and reduced leukemia cells in the peripheral blood in four PDXs, but with only one objective response. There was no obvious relationship between duvelisib efficacy and PI3Kδ or PI3Kγ expression or mutation status, nor was the in vivo response to duvelisib subtype dependent. Duvelisib demonstrated limited in vivo activity against ALL PDXs.

Patterns of IgG Testing and Rates of Hypogammaglobulinemia in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

BackgroundInfections cause substantial morbidity and up to 50% of deaths in patients with chronic lymphocytic leukemia (CLL). Hypogammaglobulinemia (HGG), a reversible risk factor for severe infections, is associated with CLL and its therapies. We evaluated patterns of immunoglobulin G (IgG) testing and immunoglobulin replacement therapy (IgRT) initiation in patients with CLL. MethodsThis retrospective, longitudinal study evaluated the real-world use of IgG testing in adults with CLL diagnosed after 2010 using deidentified clinical data from the Massachusetts General Brigham Research Patient Data Registry. Eligible patients had ≥12 months of clinical information post-CLL diagnosis and ≥3 visits/year. Timing of IgG testing, IgRT initiation, and serum IgG levels before and after IgRT initiation were examined. Results were reported with descriptive statistics including medians and interquartile range (IQR); P-values were calculated using McNemar’s test. ResultsThe cohort included 2842 patients; median (IQR) age was 69 (60, 76) years, 61.3% were men, 92.9% were White, 75.2% were treatment-naïve, and median (IQR) follow-up was 4.2 (2.2, 6.8) years. Of 1352 (47.6%) patients with IgG testing during the follow-up period, median (IQR) number of IgG tests was 0.5 (0.2,1.2) per patient/year; 34.1% had HGG (IgG < 500 mg/dL). Median (IQR) time from CLL diagnosis to first IgG test was 6.9 (0.9, 22.6) months. Number of IgG tests, IgRT administrations, timing of IgRT initiation from diagnosis and IgG testing, and serum IgG levels before and after IgRT initiation are described in the Table. Among patients with ≥1 IgRT administration, median (IQR) IgG serum levels improved and the proportion of patients with HGG decreased ≥12 months following IgRT initiation (Table). ConclusionsAs CLL treatment evolves, it is important to identify which patients are at greatest risk of infections and to standardize HGG screening. This study demonstrates that IgG levels are not assessed frequently post-CLL diagnosis, nor uniformly reassessed following initiation of IgRT. Among patients with CLL receiving IgRT, IgG levels improved after IgRT initiation. Thus, increased awareness and IgG screening might reduce severe or recurrent infections in the CLL patient population.Takeda Pharmaceuticals USA, Inc. funded the study and writing support.

Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial.

This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2-8) cycles. Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.

Efficacy and Safety of Bruton Tyrosine Kinase Inhibitor Monotherapy Compared with Combination Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Systematic Review and Meta-Analysis.

The effectiveness and safety of combination treatments such as chemoimmunotherapies in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) remain controversial. Bruton tyrosine kinase inhibitors (BTKis) are an effective therapy for CLL/SLL patients. This meta-analysis aimed to compare the efficacy and safety of BTKis versus combination therapy in CLL/SLL patients. We searched the PubMed, Cochrane, Medline, and Embase databases through February 2023 for relevant randomized controlled trials (RCTs). Four RCTs (including 1510 patients) were found and met the inclusion criteria. Progression-free survival (PFS) was significantly improved with BTKis when compared to the combination therapy (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.22-0.40), while a pooled analysis of overall survival did not favor single-agent BTKis over the combination therapy (HR, 0.87; 95% CI, 0.67-1.15). We observed consistent benefits for PFS among patients with high-risk disease characteristics. Although there was no difference in complete response between the two arms (risk ratio (RR), 0.54; 95% CI, 0.20-1.46), BTKi use was related to a better overall response rate (RR, 1.10; 95% CI, 1.04-1.16). The risk of grade ≥3 adverse events (AEs) was comparable between the two arms (RR, 0.82; 95% CI, 0.55-1.23). However, the risk of grade ≥3 AEs was significantly lower in the second-generation BTKi group than in the combination therapy group (RR, 0.73; 95% CI, 0.54-0.98). Overall, BTKis have superior efficacy compared to the combination regimens in patients with untreated or treated CLL/SLL without excess toxicity. Further studies are needed to confirm these results and determine the optimal therapy for managing patients with CLL/SLL.