Citations

Abstract The receptor tyrosine kinase AXL is a member of the TYRO3, AXL, and proto-oncogene tyrosine-protein kinase MER family and plays pleiotropic roles in cancer progression. AXL is expressed in immunosuppressive cells, which contributes to decreased efficacy of immunotherapy. Therefore, we hypothesized that AXL inhibition could serve as a strategy to overcome resistance to chimeric antigen receptor T (CAR T)–cell therapy. To test this, we determined the impact of AXL inhibition on CD19-targeted CAR T (CART19)–cell functions. Our results demonstrate that T cells and CAR T cells express high levels of AXL. Specifically, higher levels of AXL on activated Th2 CAR T cells and M2-polarized macrophages were observed. AXL inhibition with small molecules or via genetic disruption in T cells demonstrated selective inhibition of Th2 CAR T cells, reduction of Th2 cytokines, reversal of CAR T-cell inhibition, and promotion of CAR T-cell effector functions. AXL inhibition is a novel strategy to enhance CAR T-cell functions through two independent, but complementary, mechanisms: targeting Th2 cells and reversing myeloid-induced CAR T-cell inhibition through selective targeting of M2-polarized macrophages.

12057 Background: AlthoughCLL primarily affects older adults (median age 71 years), limited data exists about the outcomes of adults who are ≥80 years old because they are under-enrolled on clinical trials. Methods: The Mayo Clinic CLL Database was used to conduct a retrospective cohort study of adults ≥80 years at the time of frontline CLL treatment. Kaplan-Meier analysis was used to plot OS, and cumulative incidence was used to plot TTNT, accounting for competing risk of death. The Mayo Clinic IRB approved the study. Results: Our study included 216 patients with CLL who were age ≥80 years at the time of frontline CLL therapy between 1/1995 and 11/2022 (Table). The median time from CLL diagnosis to initiation of frontline therapy was 3.1 years. The median OS after start of frontline therapy was 3.9 years. The median OS was 3.3 years (95% CI 2.6–4.2) for patients who received alkylating agents (e.g., chlorambucil, n=96), 3.8 years (95% CI 2.8–not reached [NR]) for purine analogues (e.g., fludarabine, n=11), 3.9 years (95% CI 3.2–4.9) for anti-CD20 monoclonal antibody monotherapy (e.g., obinutuzumab, n=64), and not reached (95% CI 3.3-NR) for novel agents (n=43) (P=0.02). The types of novel agents included ibrutinib (n=19), acalabrutinib (n=16), venetoclax (n=7), and orelabrutinib (n=1). There was no difference in OS between 36 patients who received a BTKi compared to the 7 patients who received venetoclax-based therapy. At a median follow-up time of 6.7 years from the first visit, 143 patients died from the following: progressive CLL (n=63), infections (n=12), other cancer (n=11), non-CLL reasons (n=21). Cause of death was unavailable for 36 patients. On multivariable analyses, older age (i.e., any 5-year increase in age) was associated with a 50% increased risk of death (HR 1.5, 95% CI 1.2-1.9, p=0.001), and treatment with non-novel agents was associated with 3.2 times increased risk of death (HR 3.2, 95% CI 1.2-8.9, p=0.02). Of the 216 patients, 76 patients required second-line therapy; the median TTNT was 4.2 years (95% CI 2.9-NE). The most used second-line agents were monoclonal antibodies alone (20/76, 26%) and single-agent alkylators (18/76, 24%). Conclusions: When compared to all other CLL treatments, novel agents such as BTKi and venetoclax-based treatments are associated with significantly improved OS in patients with CLL ≥80 years old when used in the frontline setting. [Table: see text]

e19507 Background: Patients (pts) with CLL are at elevated risk of developing non-hematologic malignancies. Radiation therapy (RT) is a critical component of management in localized solid organ malignancies. Novel agents (NA) are widely used in CLL treatment; however, safety data are lacking to guide treatment of pts requiring concurrent RT and NA. Methods: We identified pts treated concurrently with NA for CLL and RT for second primary malignancy (SPM) at Mayo Clinic from 2014-2022. Adverse events within 3 months of RT were evaluated using the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematological toxicity and the Common Terminology Criteria for Adverse Events (CTCAE) version 5 for non-hematological toxicity. Patients without seamless, concurrent treatment with NA and RT were excluded. Results: Twenty-six pts were included. NA therapy consisted of ibrutinib (n = 23), acalabrutinib (n = 2), and venetoclax (n = 1). Median follow up time since RT completion was 1.5 years. The median age at NA initiation was 67 years (range:46-85) and at RT start was 68 years (range: 51-85); 92% of pts were male. NA was first treatment in 23% of pts; the median number of prior lines of therapy was 1 (range: 0-4). IGHV was unmutated in 82% and TP53 aberration was present in 24% of evaluable patients. SPM sites included prostate (n = 9), head/neck (n = 8), lung (n = 3), and brain, breast, bone, skin, kidney, and thymus (n = 1 each). The most common conventionally fractionated prescriptions (cGy/fx) were 6000/30 (n = 6) and > 6000-7020/20-33 (n = 7). SBRT ranged from 3300/5 to 5400/3 (n = 8). Five pts received other, varied RT prescriptions. Overall, 3 (12%) pts experienced at least one grade 3/4 toxicity. Grade 3/4 thrombocytopenia was observed in 2 (8%) pts and grade 3/4 neutropenia was observed in 2 pts per iwCLL criteria. Grade ≥3 non-hematological toxicities occurred in two pts that required hospitalization for critical illness, including 1 pt with grade 5 respiratory failure within 6 weeks after RT. Dose de-escalation of ibrutinib was reported in one case for pancytopenia attributed to use of a radiosensitizing agent. There were no cases of RT dose modification. Conclusions: Continuing NA CLL therapy during RT did not result in unexpected toxicities. This approach may maintain CLL disease control without compromising management of the SPM. [Table: see text]

7500 Background: The Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib +/- anti-CD20 antibody obinutuzumab (IO) is a standard frontline regimen for older adults with CLL. BTKi alone do not often lead to complete response (CR) or undetectable minimal residual disease (uMRD), thus are given indefinitely. Smaller trials showed that IO plus venetoclax (IVO) can induce uMRD CRs which may allow successful discontinuation. Methods: Alliance for Clinical Trials in Oncology A041702 is a multicenter trial designed to evaluate if IVO with response-guided discontinuation of I improves progression free survival (PFS) versus IO with indefinite I in treatment-naïve, older CLL pts. IO is given in standard fashion, and in the IVO arm V is added at C3D1 and continued until C14D28. After 14 cycles, pts undergo response evaluation including CT scans and bone marrow biopsy with central MRD assessment by flow cytometry. Pts in IVO arm with uMRD CR discontinue I; all others continue I until progression or unacceptable toxicity. Eligible pts were age ≥70 years (amended to ≥65). Pts had CrCl ≥ 40 mL/min, bilirubin ≤ 1.5 x ULN, and no other life-limiting intercurrent illness. Pts were stratified based on Rai stage and +/- del17p13.1 by FISH, and randomized 1:1 to IO:IVO. With 431 evaluable pts, the trial had 90% power to detect significant improvement in PFS using a one-sided log-rank test with one-sided type 1 error rate of 2.5%. The Alliance DSMB approved release of data on Nov 4, 2022 after meeting the protocol defined futility threshold at the second planned event-driven interim analysis. Data were locked on December 15, 2022. Results: Between January 4, 2019 and July 15, 2022, 465 pts were registered (IO:232, IVO:233). Median age was 74; 67% of pts were men. Rai stage 3-4 was seen in 55% and del17p in 13%. With median follow-up of 14 months, PFS of IO was 87.5% compared to 85% on IVO. Events were observed in 29 pts on IO (4 progressions, 23 deaths, 2 pts started other therapy) and 35 on IVO (7 progressions, 28 deaths). The predefined futility boundary was crossed, with a hazard ratio (HR) of 1.20 (95% CI: 0.73-1.97) in favor of IO. COVID-19 was the leading cause of death in both arms, (11 COVID-19 deaths on IO, 19 on IVO), with 13 and 11 additional deaths from other causes, respectively. Censoring pts with COVID-19 related deaths, PFS HR is 0.82 (95% CI: 0.44-1.53) in favor of IVO. Grade 3+ toxicity and discontinuation in year 1 of therapy were similar between arms. Conclusions: This study demonstrates that PFS for IVO is not superior to IO for treatment-naive older CLL pts in the setting of the COVID-19 pandemic. Study treatment is ongoing, and long-term follow-up will determine if there are advantages to IVO, with special attention to MRD and therapy discontinuation. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03737981 .

Abstract TP53 aberrations, including mutations and deletion of 17p13, are important adverse prognostic markers in chronic lymphocytic leukemia (CLL) but are less studied in high count monoclonal B-cell lymphocytosis (HCMBL), an asymptomatic pre-malignant stage of CLL. Here we estimated the prevalence and impact of TP53 aberrations in 1,230 newly diagnosed treatment-naïve individuals (849 CLL, 381 HCMBL). We defined TP53 state as: wild-type (no TP53 mutations and normal 17p), single-hit (del(17p) or one TP53 mutation), or multi-hit (TP53 mutation and del(17p), TP53 mutation and loss of heterozygosity, or multiple TP53 mutations). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time to first treatment and overall survival by TP53 state. We found 64 (7.5%) CLL patients and 17 (4.5%) HCMBL individuals had TP53 mutations with variant allele fraction >10%. Del(17p) was present in 58 (6.8%) of CLL and 11 (2.9%) of HCMBL cases. Most individuals had wild-type (N=1,128, 91.7%) TP53 state, followed by multi-hit (N=55, 4.5%) and then single-hit (N=47, 3.8%) TP53 state. The risk of shorter time to therapy and death increased with the number of TP53 abnormalities. Compared to wild-type patients, multi-hit patients had 3-fold and single-hit patients had 1.5-fold increased risk of requiring therapy. Multi-hit patients also had 2.9-fold increased risk of death compared to wild-type. These results remained stable after accounting for other known poor prognostic factors. Both TP53 mutations and del(17p) may provide important prognostic information for HCMBL and CLL that would be missed if only one were measured.

Abstract Preclinical studies have shown augmented activity when combining Bruton tyrosine kinase inhibitors (BTKi) with inhibitors of mammalian target of rapamycin (mTOR) and immunomodulatory agents (IMiD). We conducted a phase 1, open‐label study at five centers in USA to evaluate the safety of triplet BTKi/mTOR/IMiD therapy. Eligible patients were adults aged 18 years or older with relapsed/refractory CLL, B cell NHL, or Hodgkin lymphoma. Our dose escalation study used an accelerated titration design and moved sequentially from single agent BTKi (DTRMWXHS‐12), doublet (DTRMWXHS‐12 + everolimus), and then to triplet therapy (DTRMWXHS‐12 + everolimus + pomalidomide). All drugs were dosed once daily on days 1–21 of each 28‐day cycle. The primary goal was to establish the recommended phase 2 dose of the triplet combination. Between September 27, 2016, and July 24, 2019, a total of 32 patients with a median age of 70 years (range 46 to 94 years) were enrolled. No MTD was identified for monotherapy and the doublet combination. The MTD for the triplet combination was determined to be DTRMWXHS‐12 200 mg + everolimus 5 mg + pomalidomide 2 mg. Responses across all studied cohorts were seen in 13 of 32 (41.9%). Combining DTRMWXHS‐12 with everolimus and pomalidomide is tolerable and shows clinical activity. Additional trials could confirm benefit of this all‐oral combination therapy for relapsed/refractory lymphomas.

Abstract The consequences of immune dysfunction in B-Chronic Lymphocytic Leukemia (CLL) likely relate to the incidence of serious recurrent infections and second malignancies that plague CLL patients. The known immune abnormalities are not able to consistently explain these complications and it is not easy to correct their immune status. Here, we report bone marrow (BM) hematopoietic dysfunction in early and late stage untreated CLL patients. We found reduced functional capacity of hematopoietic progenitors in BM using colony forming unit assays and flow cytometry revealed significant reductions in frequencies of hematopoietic stem and progenitor cell (HSPC) populations. Consistent with the reduction in HSPCs, monocytes and natural killer cells in BM were reduced and the reduction in BM was recapitulated in blood. Finally, we report imbalances in protein levels of the transcriptional regulators HIF-1α, PU.1, and GATA-2 in CLL patient BM, providing molecular insight into the basis of HSPC dysfunction. Importantly, PU.1 and GATA-2 were rapidly increased when healthy HSPCs were exposed in vitro to TNFα, a cytokine constitutively produced by CLL B cells. Together, these findings reveal BM hematopoietic dysfunction in untreated CLL patients, adding to the complex immunodeficiency state of these patients and the reduced capacity of the innate immune system.