Wiestner, Adrian U.

Abstract Background CLL International Prognostic Index (CLL-IPI) is a weighted scoring system combining five prognostic factors that was developed for risk stratification of TN CLL in the era of chemoimmunotherapy [CLL-IPI Working Group. Lancet Oncol 2016]. Recently, the four-factor model (CLL4) was validated in patients (pts) receiving ibrutinib, primarily for the treatment of relapsed or refractory CLL [Ahn et al. J Clin Oncol 2021]. Data on model performance are limited when ibrutinib is used as first-line therapy. Here we evaluated CLL4 and CLL-IPI in TN CLL pts aged 65 years or older in the Alliance A041202 trial (NCT01886872) [Woyach et al. N Engl J Med 2018]. Methods Pts were randomized to bendamustine plus rituximab (BR group) or ibrutinib-based therapy with or without rituximab (I/IR group). The CLL4 score was determined for individual pts by assigning 1 point each to the presence of TP53 aberration, β-2 microglobulin (B2M) ≥5 mg/L, elevated lactate dehydrogenase (LDH), and prior treatment, and summing over points; risk categories were low (0-1), intermediate (2), and high (3-4). We utilized the first three factors of CLL4 since all pts were previously untreated. The CLL-IPI score was determined based on the presence of TP53 aberration (4 points), B2M >3.5 mg/L (2 points), unmutated IGHV (2 points), age >65 years (1 point), and Rai stage I-IV (1 point), and summing over points; risk categories were low (0-1), intermediate (2-3), high (4-6), and very high (7-10). Two of five CLL-IPI risk factors contributed little information since all pts had Rai stage I-IV and nearly all had age >65 years. The primary endpoint for risk stratification was progression-free survival (PFS). We used Kaplan-Meier estimates and Cox proportional hazards models for analyses. Results Of 547 pts randomized, 472 pts had a complete set of data required for the calculation of CLL4 scores. The median age was 71 years, and 92% were older than 65 years. 12% had TP53 aberration including deletion 17p and TP53 mutation. Of 334 pts with known IGHV status, 61% had unmutated IGHV. The median follow-up for PFS was 4.5 years. In these 472 pts, 359 (76%) were low risk, 99 (21%) intermediate risk, and 14 (3%) high risk. In the BR group, PFS was significantly shorter for intermediate/high risk CLL4 than low risk (HR 2.43, 95% CI 1.55-3.79, p=0.0001). However, differences in PFS were less apparent for the I/IR group (HR 1.60, 95% CI 1.00-2.56, p=0.05). In 334 pts in whom CLL-IPI scores could be calculated, 6 (2%) were low risk, 38 (11%) intermediate risk, 262 (78%) high risk, and 28 (8%) very high risk. In the BR group, PFS was significantly shorter for high risk CLL-IPI than intermediate risk (HR 3.73, 95% CI 1.16-12.04, p=0.03) and for very high risk CLL-IPI than high risk (HR 6.05, 95% CI 2.80-13.08, p<0.0001). However, there were no significant PFS differences for the I/IR group (high risk CLL-IPI vs intermediate risk: HR 1.33, 95% CI 0.53-3.33, p=0.54; very high risk CLL-IPI vs high risk: HR 1.21, 95% CI 0.48-3.02, p=0.69). We next assessed individual components of the prognostic models in the 334 pt subset including both BR and I/IR groups (Table). Variables significantly associated with PFS were B2M, elevated LDH, and unmutated IGHV when controlling for the treatment group. In contrast, TP53 aberration conferred a poor prognosis in the BR group, but not in the I/IR group (interaction test, p=0.008), indicating first-line therapy with ibrutinib can improve the outcome of TP53 aberrant CLL to levels seen in pts without the aberration. In a multivariable model, the interaction between TP53 aberration and the treatment group remained significant. All adverse risk factors except elevated LDH maintained their independent prognostic value. Conclusions Neither CLL4 nor CLL-IPI effectively discriminated PFS of older adults receiving ibrutinib-based therapy for TN CLL. When given as a first-line treatment, ibrutinib can overcome the poor prognostic impact of TP53 aberration. IGHV mutation status and B2M had independent prognostic value in our dataset. Support: U10CA180821, U10CA180882, U24CA196171; Pharmacyclics, An AbbVie Company Clinicaltrials.gov identifier: NCT01886872 Figure 1 Figure 1. Disclosures Ruppert: Telios Pharma: Consultancy. Wiestner: Merck: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding; Nurix: Research Funding; Genmab: Research Funding. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Byrd: Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria. Stone: AbbVie: Consultancy; Jazz: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Janssen: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; Novartis: Consultancy, Research Funding; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; GlaxoSmithKline: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Boston Pharmaceuticals: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding.

Background : The presence of TP53 aberrations (defined as del(17p) or TP53 gene mutation) is a strong negative predictor of survival in patients (pts) with CLL. First-line chemoimmunotherapy is suboptimal in pts with CLL bearing TP53 aberrations, with 3-year progression-free survival (PFS) and overall survival (OS) rates of only 18% and 38%, respectively, with fludarabine, cyclophosphamide, and rituximab (Hallek, Lancet 2010). Ibrutinib is the only once-daily Bruton's tyrosine kinase (BTK) inhibitor with significant PFS and OS benefit demonstrated in multiple randomized phase 3 studies (eg, RESONATE-2, ECOG1912) in the first-line treatment of CLL/small lymphocytic lymphoma (SLL). Previous reports of single-agent ibrutinib or ibrutinib-based combination treatments have further demonstrated favorable PFS benefit in pts with TP53 aberrations in both the first-line and relapsed/refractory settings. Despite these study-specific subgroup analyses, there are limited data on long-term outcomes in pts with TP53 aberrations treated with first-line BTK inhibitors. We performed a pooled analysis of data across 4 studies to evaluate the long-term efficacy and safety of first-line ibrutinib-based therapy in pts with CLL bearing TP53 aberrations. Methods : Data for first-line ibrutinib treatment in pts with TP53 aberrations were pooled across 4 clinical trials in CLL/SLL: PCYC-1122e (NCT01500733; single-agent ibrutinib; n=34), PCYC-1130 (NCT02264574; ibrutinib + obinutuzumab; n=18), ECOG1912 (NCT02048813; ibrutinib + rituximab; n=26), and RESONATE-2 (NCT01722487; single-agent ibrutinib; n=11). ECOG1912 and RESONATE-2 excluded pts with del(17p) but did not exclude pts with TP53 mutations. Long-term PFS (assessed by investigator), OS, and safety are reported. Results : Eighty-nine pts with TP53 aberrations receiving first-line ibrutinib treatment were included in this pooled analysis. Median age was 65 years (range 33-87), and 69% of pts were male. At baseline, 53% had Rai stage III/IV, 38% had bulky disease (lymph nodes ≥5 cm), and 69% (of 87 evaluable) had unmutated IGHV. All patients had either del(17p) or TP53 mutation; 53% (of 89 evaluable) had del(17p) and 91% (of 58 evaluable) had TP53 mutation. Among 16 pts with del(17p) who had TP53 sequencing results available, 11 (69%) had both del(17p) and TP53 mutation. Forty-five pts received ibrutinib as a single agent and 44 received ibrutinib in combination with an anti-CD20 agent. With a median follow-up of 50 months (range 0.1 to 95.9 months), median PFS was not reached (95% CI: 67 months to not estimable; Figure 1A). At 48 months, the PFS rate was 79% and the OS rate was 88% (Figure 1B). Median duration of ibrutinib treatment was 46 months (range 0.1 to 95.5 months). Reasons for treatment discontinuation were progressive disease (20%), study closure (12%), adverse event (10%), withdrawal by pt (7%), death (3%), and other (physician decision due to scheduled pt surgery; 1%). Grade ≥3 adverse events of clinical interest with up to 8 years of treatment with ibrutinib were infection (22%; most commonly pneumonia in 7%), hypertension (13%), atrial fibrillation (12%), and major hemorrhage (7%). With the current follow-up, 46% of pts with TP53 aberrations remained on ibrutinib treatment. Conclusions : With a median follow-up of 4 years, first-line ibrutinib-based treatment resulted in sustained efficacy with high PFS and OS rates in CLL pts with TP53 aberrations, a population with historically poor outcomes. Although pts with TP53 aberrations remain at risk for progression, first-line treatment with ibrutinib has partially overcome the poor prognosis in this high-risk population with 4-year PFS and OS rates of 79% and 88%, respectively. No new safety signals were identified in this analysis. These results from a large, pooled, multi-study dataset demonstrated the long-term benefit of first-line ibrutinib-based treatment in pts with TP53 aberrations. Disclosures Allan: Janssen, AbbVie, and AstraZeneca: Other: Travel/accommodations/expenses; Celgene, Genentech, AstraZeneca, TG Therapeutics, and Janssen: Research Funding; AstraZeneca, Pharmacyclics LLC, an AbbVie Company, Genentech, AbbVie, Ascentage, and Cellectar: Consultancy; Janssen, AstraZeneca, and AbbVie: Honoraria. Shanafelt:Genentech, Pharmacyclics LLC, an AbbVie Company, AbbVie, GlaxoSmithKline, and Merck: Research Funding; Mayo Clinic: Patents & Royalties: and other intellectual property. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Moreno:Janssen, AbbVie, Sunesis, and AstraZeneca: Consultancy; AbbVie and Janssen: Research Funding; Janssen: Speakers Bureau. O'Brien:Eisai: Consultancy; Juno Therapeutics: Consultancy; Aptose Biosciences: Consultancy; GlaxoSmithKline: Consultancy; Sunesis: Research Funding; Acerta: Research Funding; Amgen: Consultancy; Celgene: Consultancy; Pfizer: Research Funding; Pharmacyclics: Research Funding; Astellas: Consultancy; Gilead: Consultancy; TG Therapeutics: Research Funding; Vida Ventures: Consultancy; KITE: Research Funding; Vaniam Group LL: Consultancy; Alexion: Consultancy; Regeneron: Research Funding; AbbVie: Consultancy; Verastem: Consultancy; Janssen Oncology: Consultancy. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Liu:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Dean:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Lai:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie and Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Other: Travel/accommodations/expenses.

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.