Chronic Lymphocytic Leukemia Or Small Lymphocytic Lymphoma Research Articles

Recent Patterns of Care with BTK Inhibitors and Distribution of Social Determinants of Health Among Patients with CLL/SLL in the US Community Setting

BACKGROUND: The treatment landscape for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) has shifted with the introduction of second-generation Bruton tyrosine kinase (BTK) inhibitors. Few real-world studies, however, have examined sequencing patterns among BTK inhibitors for CLL/SLL and the patient characteristics across different sequences, including social determinants of health (SDOH). The aim of this study is to examine the characteristics, treatment patterns, and SDOH among patients with CLL/SLL who received BTK inhibitors in a large network of community oncology practices. METHODS: This was a retrospective study of adult patients diagnosed with CLL/SLL who were prescribed a BTK inhibitor between 1/1/2020-4/30/2023 in The US Oncology Network. Study data were captured from structured fields in the iKnowMed electronic health record (EHR), with linkage to external sources to evaluate patients' Area Deprivation Index (ADI) scores and rural/urban status. ADI scores were determined by mapping patients' home addresses to a census block group (CBG), which was then linked to the ADI. ADI rankings are based on CBG and determined by the domains of income, education, employment, and housing quality, where high scores indicate increased disadvantage. Low socioeconomic status (SES) was defined as the top 20% of ADI scores on a national and state level (cut-off based on literature review). Rural/urban status was based on the RUCA codes published by the US Department of Agriculture. Insurance coverage was reported “as is” in the claims system with Medicaid an indicator of low SES. Results were assessed by treatment sequence, and SDOH measures results were reported as counts, frequency, and 95% confidence intervals (CI). Chi Square p-values were reported for selected SDOH measures and are shown in text. Data are presented for treatment subgroups with at least 30 eligible patients. RESULTS: In total, 2,082 patients were included in the analysis (median age 73 years; 61.9% male; 73.5% white; 35.0% Rai stage 0-I; median follow-up 14.1 months). The highest proportion of patients received acalabrutinib or ibrutinib without an observed subsequent BTK inhibitor (n=1,159 and n=628, respectively). Patient characteristics by the top 6 treatment sequences are provided in Table 1. Demographic and clinical characteristics across the treatment sequences were similar, including sex, race, and ethnicity distributions, along with Rai stage and ECOG performance status at baseline. Across the subgroups, 8.7% (n=182) were observed to receive a subsequent BTK inhibitor. Among patients who received a BTK inhibitor in 2020 (n=597), 62.3% (n=372) received ibrutinib and a single patient received zanubrutinib. Among the 206 patients who received a BTK inhibitor in 2023, 6.8% (n=14) and 28.6% (n=59) received ibrutinib and zanubrutinib, respectively. In total, 137 patients (6.6%; 95% CI 5.6-7.7) were classified as living in rural locations. Low SES status based on state and national indicators was observed among 361 (17.3%; 95% CI 15.7-19.0) and 125 (6.0%; 95% CI 5.0-7.1) patients, respectively, and was also similar across the subgroups. The highest proportion of patients had Medicare insurance coverage (42.1%; n=877; 95% CI 40-44.3), followed by managed Medicare (24.4%; n=508; 95% CI 22.6-26.3). A statistical difference was found between the treatment regimens for rural/urban ( P<0.01), but not for state ADI ( P=0.52), national ADI ( P=0.36), or Medicaid insurance coverage vs. all others ( P=0.18). The actual values for each regimen are in the Table 1. CONCLUSIONS: The results of this study provide insight into the shifting treatment landscape of BTK inhibitor use among patients with CLL/SLL. During the observation period, the use of ibrutinib decreased while acalabrutinib and zanubrutinib increased. When evaluating measures of SDOH, similarities across the treatment sequence subgroups suggest that patients' SES and Medicaid do not influence prescribing patterns, but rural/urban status show differences. Further real-world research and longitudinal follow-up are needed to examine the impact of SDOH on treatment choice, treatment switching, reasons for switching, and outcomes among users of BTK inhibitors. Additionally, a better understanding of the specific treatment regimen(s) and reasons driving rural/urban differences is needed.

Multicenter Study to Assess the Outcomes and Prognosis of Richter's Transformation in the Era of Novel Agents and Cell Therapy

INTRODUCTION: Richter's transformation (RT) is the transformation of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RT occurs in 2-10% of CLL patients, usually between 2-5 years after CLL diagnosis. The prognosis of RT is poor and the historical median overall survival (OS) after diagnosis is about 8-14 months. However, with the development of novel therapeutic agents including Bruton tyrosine kinase inhibitors (BTKi) and anti-CD19 CAR T-cell therapy, the natural history and prognosis of RT have evolved. To date there is limited data on the prognosis and management of RT in the era of novel therapies. To better understand the prognosis, impact of new therapeutics, and survival for RT in the modern era we performed a multicenter retrospective study to assess the outcomes of RT. METHODS: We performed a multicenter retrospective study including 4 US centers evaluating patients who were diagnosed with RT between 2012-2022 with the current analysis limited to those patients with large B-cell lymphoma transformation. Statistical analyses include descriptive statistics, t-tests for normally distributed continuous variables, non-parametric tests for skewed variables, and chi-square for categorical variables. Overall survival (OS) was calculated using Kaplan-Meier estimates. RESULTS: We analyzed 78 patients with DLBCL transformation from underlying CLL. The median age at RT diagnosis was 66 years (43-84 years). Most patients had advanced stage III-IV disease 92% (n=72). Extranodal disease was present in 68% (n=53). Among 31 patients with 17p deletion or p53 mutational data available at the time of CLL diagnosis, one of these findings was present in 18 patients. Patients had 2 median lines (range 0-7) of treatment for CLL prior to RT diagnosis. 49% (n=38) had BTKi exposure and 28% (n=22) had Venetoclax exposure before RT diagnosis. 24% (n=19) had no prior treatment for CLL before RT. The median time from CLL to RT diagnosis was 42.5 (0-332) months. Median lines of therapy for RT were 2 (range 1-8). The most common frontline regimens for RT included R-CHOP/ R-CHOP-like backbone in 58% (n=45) or high intensity chemoimmunotherapy regimens (R-EPOCH/CVAD) in 14% (n=11). Overall response rate (ORR) to frontline treatment was 56% (complete response (CR)=32/partial response (PR)=12). Of the patients who received 1 st line treatment and achieved a CR/PR (n=44), the 1-year duration of response (DOR) was 50% and the median DOR was 14 months. Fifty-one patients either relapsed or had refractory/progressive disease after frontline treatment and 48 patients received further treatment. Among these 48 patients, 29% (n=14) received a covalent or a non-covalent BTKi in the 2 nd or higher line setting, with an ORR of 43% (CR=4, PR=2). 23% (n=11) received venetoclax with/without other agents in the 2 nd or higher line setting, with an ORR of 36% (CR=3, PR=1). In total, 17 patients received CD19 based CAR T-cell therapy as part of treatment for RT, all in a second or later line of treatment. The ORR and CR rate to this therapy was 82% (n=14). Of these 14 responding patients, the 1-year DOR was 57% and the median DOR was not reached. 12 patients underwent allogeneic transplant (alloHCT), 11/12 as a consolidative treatment option. At first disease assessment after allo-HCT, the ORR was 92% (CR=11). Of the 11 responders, the 1-year DOR was 73% and the median DOR was 42 months. For the entire cohort (n=78), the 1-year OS was 62% and the median OS was 31 months (95% CI 22-NR), which suggest improvement compared to historical reports. CONCLUSION Although RT has a poor prognosis, with the use of novel therapies such as BTKi and CAR T-cell therapy, the overall survival of these patients has improved in the current era. The overall response to chemoimmunotherapy in the first line setting remains poor. Despite this, advances in the management of RT with incorporation of targeted and cellular therapies has improved clinical outcomes of RT. Incorporating these agents either alone or in combination with chemoimmunotherapy in the earlier setting may further improve outcomes in patients with this aggressive disease.

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]

Anti-spike antibody response to the COVID vaccine in lymphoma patients.

Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody level following the primary COVID vaccination series. The primary vaccination series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fisher's exact test, and unadjusted and adjusted logistic regression models were used for univariate and multivariate analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitt's, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined; 12 patients (5%) with mantle cell lymphoma; and 4 patients (2%) with other lymphoma types. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary vaccination series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p = 0.04). Lymphoma patients are capable of mounting a humoral response to the COVID vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population.

Results from the Phase 3 DUOTM Trial: A Randomized Comparison of Duvelisib Vs Ofatumumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Results from the Phase 3 DUOTM Trial: A Randomized Comparison of Duvelisib Vs Ofatumumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Oral PI3K-δ,γ Inhibitor for the Management of People with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Narrative Review on Duvelisib.

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.

Efficacy of Ibrutinib in Newly Diagnosed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Combined Analysis of Four Phase III Randomized Controlled Trials

Introduction: Chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), the most common adult lymphoproliferative disorder in western countries, is a B-cell malignancy that is treated based on presenting symptoms and stage. The treatment response is highly variable depending on disease stage and mutation profile of the malignant B cells. Bruton tyrosine kinase (BTK) is a downstream B-cell signaling kinase that has been shown to play a major role in B cell survival and proliferation. Hence, BTK inhibitors have become an attractive therapeutic strategy for treatment of CLL/SLL in both newly diagnosed and relapse/refractory setting. Ibrutinib is a potent oral, covalent inhibitor of BTK that has gained wide acceptance in treatment of CLL/SLL. We analyzed phase III trials where ibrutinib was used in newly diagnosed untreated CLL/SLL to examine treatment effects based on disease staging and molecular profiling. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with newly diagnosed/ untreated CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Four phase III RCTs (RESONATE-2, iLLUMINATE, E1912 and A041202 studies) with a total of 1,574 patients with newly diagnosed CLL/SLL were eligible. Studies compared ibrutinib+ obinutuzumab vs chlorambucil+ obinutuzumab, ibrutinib vs chlorambucil, bendamustine+ rituximab vs ibrutinib vs ibrutinib+ rituximab, ibrutinib+ rituximab vs fludarabine+ cyclophosphamide+ rituximab, were included in the analysis. The randomization ratio was 2:1 in E1912 study and 1:1 in other studies. The I2 statistic for heterogeneity was 75, suggesting moderate heterogeneity among RCT. The pooled HR for PFS was statistically significant at 0.28 (95% CI: 0.19-0.41; P < 0.0001). The PFS benefit was observed in all Rai stages, either del11q or del17p and unmutated or mutated IGHV status; Rai stage ≤ 2 cohort (HR, 0.29; 95% CI: 0.21- 0.41; P < 0.0001), Rai stage >2 cohort (HR, 0.31; 95% CI: 0.21- 0.46; P < 0.0001), either del11q or del17p cohort (HR, 0.19; 95% CI: 0.12- 0.31; P < 0.0001), unmutated IGHV cohort (HR, 0.18; 95% CI: 0.12- 0.27; P < 0.0001), and mutated IGHV cohort (HR, 0.27; 95% CI: 0.15- 0.49; P < 0.0001). Conclusions: Our meta-analysis showed that ibrutinib maintains activity in newly diagnosed untreated CLL/SLL, across all Rai stages, in del11q or del17p and in unmutated and mutated IGHV. The use of ibrutinib should be further explored considering other factors such as overall survival rates, detrimental side effects, and health-related quality of life for the patients. Ibrutinib clearly outlines an effective treatment option, ultimately increasing the quality of care. Disclosures No relevant conflicts of interest to declare.

Incidence of Serious Adverse Events, Pneumonitis, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Introduction: Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for multiple pathways in B cells and is important for B cell survival, proliferation and metabolism. Hence, PI3K inhibitors have become an attractive therapeutic option for treatment of B cell malignancies. Two prominent PI3K inhibitors, (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) and have shown to improve survival in recent trials with notable toxicities. We analyzed phase 3 trials to assess the incidence of serious adverse events, pneumonitis, infection and sepsis associated with PI3K inhibitors in this susceptible population. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention serious adverse events, pneumonitis, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included in analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The incidence of serious adverse events was 479 (73.69%) in study group vs 252 (44.92%) in control group (RR, 1.58; 95% CI: 1.37 - 1.83; P < 0.0001 and RD, 0.26; 95% CI: 0.13 - 0.40; P = 0.0002). Pneumonitis was noted in 20 (3.07%) vs 1 (0.18%) in control group with RR of 6.53 (95% CI: 1.74 -24.53; P = 0.005) and RD of 0.02 (95% CI: 0.01 - 0.04; P = 0.0004). The incidence of any-grade pneumonia was 107 (16.46%) in study group vs 54 (9.63%) in control group (RR, 1.61; 95% CI: 1.00 - 2.58; P = 0.05). High-grade pneumonia was reported in 81 (12.46%) in idelalisib arm versus 35 (6.24%) in control group with RR of 1.84 (95% CI: 0.82 - 4.13; P = 0.14). Pneumocystis jiroveci pneumonia (PJP) rate was 2.24% higher in study group compared to control arm (RR, 3.87; 95% CI: 1.22 - 12.29; P = 0.02). Any-grade upper respiratory tract infection (URTI) was 14% in study group versus 7.84% in control arm (RR, 1.65; 95% CI: 1.17 - 2.34; P = 0.005). Sepsis rate was 2.88% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.68 (95% CI: 1.19 - 6.04, P = 0.02). Treatment-related deaths were 64 (11.85%) in study arm vs 28 (6.17%) in control arm according to analysis of 3 trials. The pooled RR was also statistically significant at 1.87 (95% CI: 1.21 -2.88; P = 0.005). Conclusions: Our meta-analysis showed that the incidence of serious adverse events, pneumonitis, PJP pneumonia, any-grade URTI and sepsis was significantly higher in PI3K inhibitors group with RR of 1.58 for serious adverse events, RR of 6.53 for pneumonitis, RR of 3.87 for PJP pneumonia and RR of 2.68 for sepsis respectively. Moreover, patients on PI3K inhibitors experienced 5.68% higher incidence of treatment-related deaths with RR of 1.87, compared to control arm. Since treatment-related serious toxicities and deaths are higher amongst patients treated with these agents, extra caution should be observed and recommended with their use. Disclosures No relevant conflicts of interest to declare.

Final analysis from RESONATE: Six-year follow-up in patients (pts) with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) on ibrutinib.

7510 Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor, has redefined treatment paradigms for CLL/SLL. We report final analysis with up to 6 years of follow-up on ibr from the phase 3 RESONATE study of single-agent ibr vs ofatumumab (ofa) in pts with relapsed/refractory (R/R) CLL/SLL. Methods: Pts were randomized to receive oral ibr 420 mg daily until PD or intravenous ofa for up to 24 weeks. Long-term efficacy endpoints were investigator-assessed. Results: Among 391 pts randomized to receive ibr (n=195) or ofa (n=196), 86% and 79%, respectively, were in the genomic high-risk population (del(17p), del(11q), TP53 mutation, and/or unmutated IGHV). At final analysis, median follow-up was 64 mo (range, 0.3-72) on ibr. Of pts randomized to ofa, 68% crossed over to receive ibr. Significant sustained PFS benefit was observed with ibr vs ofa, with median PFS 44.1 vs 8.1 mo (HR 0.15; 95% CI 0.11-0.20; P˂0.0001) and was consistent across baseline subgroups. Median PFS in genomic high-risk population was 44.1 vs 8.0 mo on ibr vs ofa (HR 0.11; 95% CI 0.08-0.15). ORR with ibr was 88% (CR/CRi in 11%). Initial ibr treatment conferred better OS than ofa when censored for crossover (HR 0.64; 95% CI 0.42-0.98). Median duration of ibr was 41 mo (range 0.2-71); 41% of pts received ibr >4 yrs. AE profile with ibr remained consistent with prior reports. Cumulatively during long-term ibr therapy, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of pts, respectively; major hemorrhage occurred in 10%. Most common reasons for ibr discontinuation (DC) prior to study closure were PD (37%) and AEs (16%); DC due to AEs occurred in 6%, 3%, 4%, 4%, 6% and 4% of pts during yrs 0-1, 1-2, 2-3, 3-4, 4-5 and 5-6, respectively. Conclusions: With up to 6 years of follow-up, extended ibr treatment showed sustained efficacy in pts with R/R CLL, including in pts with high-risk genomic features. Safety remained acceptable with low rates of DC due to AEs, and with no new safety signals over long-term therapy. These results establish long-term benefit and tolerability for continuous ibr treatment in pts with R/R CLL. Clinical trial information: NCT01578707.

TRANSCEND CLL 004: Minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (Liso-Cel; JCAR017), a CD19-directed CAR T cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

7501 Background: Eradication of MRD in CLL patients may be necessary for deep and durable responses. We assessed safety, pharmacokinetics, and efficacy of liso-cel, an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase 1/2 TRANSCEND CLL 004 study. Methods: Eligible pts had CLL/SLL, received ≥2 prior lines of therapy (including Bruton’s tyrosine kinase inhibitors [BTKi] unless medically contraindicated), and had ECOG PS ≤1. Post lymphodepleting chemotherapy, pts received liso-cel infusion at either dose level (DL)1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Patients were monitored for dose-limiting toxicities (DLTs). Response was assessed by iwCLL 2008 criteria. MRD was assessed by flow cytometry in blood (10−4) and by NGS in bone marrow (BM; 10−6). Results: At data cutoff, 16 pts received liso-cel: DL1, n = 6; DL2, n = 10. 75% of pts had high-risk features ( TP53 mutation, complex karyotype, or del17p); 100% had prior ibrutinib and 50% had prior venetoclax. Median (range) number of prior lines of therapy was 4.5 (2‒11). There was 1 DLT of grade (G) 4 hypertension (DL2). The most common G3/4 treatment-emergent adverse events were cytopenias (thrombocytopenia, 75%; anemia, 69%; neutropenia, 63%; leukopenia, 56%). 1 pt had G3 cytokine release syndrome (CRS); 3 pts had G3 neurological events (NE). Best overall response rate (ORR) in 15 evaluable pts was 87% (13/15). 7 pts (47%) achieved complete remission with/without complete blood count recovery (CR/CRi). ORR at 6 mo was 83% (5/6). 10/15 pts (67%) achieved undetectable MRD (uMRD) in blood by day 30 and in 7/8 pts (88%) in BM. MRD-negative CRs were seen in patients who had failed both BTKi and venetoclax. Median time to peak blood CAR+ T cell level was 16 days (4‒30). Conclusions: In this study of heavily pretreated pts with standard- and high-risk CLL/SLL and previous ibrutinib treatment, liso-cel-related toxicities (ie, CRS and NEs), were manageable. Pts rapidly achieved CR/CRi and uMRD. Additional follow-up will be presented. Clinical trial information: NCT03331198.

Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab As First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE

Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab As First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE

Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes.

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.

Detection of Hodgkin Transformation in a Case of Chronic Lymphocytic Leukemia by PET/CT.

Richter’s transformation (RT) represents the development of high grade lymphoma, most commonly diffuse large B-cell lymphoma, in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). CLL/SLL may convert also to Hodgkin’s lymphoma, the so-called Hodgkin’s variant of Richter transformation. Histopathological proof is needed to confirm a definitive diagnosis. Patients with RT generally have a poor prognosis, with prompt recognition optimise clinical management. Whole-body PET scan with 18F-FDG can be used for detection of RT of CLL/SLL. We describe the case of 64-year-old woman with CLL/SLL who developed Hodgkin lymphoma detected with PET/CT.

Pleiotropy of cancer susceptibility variants on the risk of non-Hodgkin lymphoma: the PAGE consortium.

BackgroundRisk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy).ObjectiveWe investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer.MethodsAs part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative) for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies.ResultsThe analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR = 1.29, p = 0.013; DLBCL OR = 1.23, p = 0.013; NHL OR = 1.22, p = 5.9×E-05). In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in TERT: OR per C allele = 0.89, p = 3.7×E-03; rs4975616 in TERT: OR per A allele = 0.90, p = 0.01; rs3131379 in MSH5: OR per T allele = 1.16, p = 0.03), prostate (rs7679673 in TET2: OR per C allele = 0.89, p = 5.7×E-03; rs10993994 in MSMB: OR per T allele = 1.09, p = 0.04), and breast (rs3817198 in LSP1: OR per C allele = 1.12, p = 0.01) cancers, but none of these associations remained significant after multiple test correction.ConclusionThis study does not support strong pleiotropic effects of non-NHL cancer risk variants in NHL etiology; however, larger studies are warranted.

Small Lymphocytic Lymphoma Presenting as Multiple Lymphomatous Polyposis

Multiple Lymphomatous Polyposis (MLP) is characterized by multiple polyps with lymphoma invasion involving long segments of the Gastrointestinal (GI) tract. Most MLP are thought to represent Mantle Cell Lymphoma (MCL) of the GI tract. However, some follicular lymphomas, mucosa-associated lymphoid tissue lymphomas, and adult T-cell lymphomas [5] have been found to show a multiple polypoid appearance throughout long segments of the GI tract. We report a case with MLP associated with Small Lymphocytic Lymphoma (SLL). SLL in extranodal sites is difficult to diagnose and the clinical course is different from that of MCL. MCL has a more aggressive clinical course than Chronic Lymphocytic Leukemia or SLL (CLL/SLL). A median survival time of CLL/SLL is 7 to 10 years, while patients with MCL have a median survival of 3 years .

MBL: mostly benign lymphocytes, but…

In this issue of Blood, Fazi and colleagues have asked important questions and added several new observations to our understanding of monoclonal B-cell lymphocytosis(MBL) in its role as the precursor state of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

High-Grade Transformation of Low-Grade Non-Hodgkin's Lymphomas: Mechanisms of Tumor Progression

In the natural history of low-grade non-Hodgkin's lymphomas (NHL) a prolonged indolent phase of the disease may be followed by clinical progression toward intermediate and high-grade disease. The abrupt appearance of diffuse large cell lymphoma (DLL) in patients with low-grade NHL is usually associated with an accelerated clinical course and shorter time of survival. The histologic transformation has been described for chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and lymphoma of mucosa-associated lymphoid tissue (MALT). Although the histological transformation of low-grade lymphomas are relatively frequent, the clonal relationship between the two neoplasms and pathogenetic mechanisms underlying the progression of the disease are widely debated. In this review, we will focus on the possible relationship between the low-grade and the transformed high-grade NHLs and genetic lesions that may be associated with the histologic transformation and clinical progression of the disease.

Authors' reply

<h3>Abstract</h3> Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. There is limited data on the efficacy of the COVID vaccines in lymphoma patients, and to suggest the optimal timing of vaccination to elicit immunity in patients receiving immunochemotherapy. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody titer following the primary COVID vaccination series. The primary series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fisher’s exact test, and unadjusted and adjusted logistic regression models were used for univariate (UVA) and multivariate (MVA) analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitt’s, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); and 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p=0.04). Lymphoma patients are capable of mounting a humoral response to the COVID mRNA vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population.