TP53 mutation + Chr del(17p)

Introduction : The combination of venetoclax, the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL) (Wierda et al. Other secondary endpoints include PFS as assessed by investigator (INV); CRR by INV; rate of uMRD4 based on flow cytometry; overall response rate by IRC and INV; duration of response by IRC and INV; patient-reported outcomes; and safety and tolerability. Recruitment is ongoing at approximately 230 study sites in 20 countries, including 50 sites in the US, 6 in Brazil, and 15 in Canada.

Introduction : Combined treatment with covalent BTK-inhibitor (cBTKi), such as ibrutinib, acalabrutinib, or zanubrutinib with BCL2-inhibitor, venetoclax, +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectable MRD (U-MRD4, 10-4 sensitivity) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). Adverse event profile was similar to what was noted in previous studies with these agents. Updated data will be presented.

Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs six cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile.

The combination of venetoclax (ven), the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has efficacy in CLL. Other secondary endpoints include investigator (INV)-assessed PFS, CRR-INV, uMRD4 rate by flow cytometry, ORR-IRC and -INV, DOR-IRC and -INV, patient-reported outcomes, and safety and tolerability. Recruitment is ongoing.

Background: Treatment with combined covalent BTK-inhibitor (cBTKi such as ibrutinib, acalabrutinib, zanubrutinib) withBCL2-inhibitor, venetoclax +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectableMRD (U-MRD) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report the first results for first-line combined pirtobrutinib, venetoclax, and obinutuzumab in pts with CLL. Avery high rate of bone marrow U-MRD at 10-6 sensitivity was noted at 6-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents.

Zanubrutinib, a next-generation BTK inhibitor, significantly improved PFSand had a more tolerable safety profile, including fewer cardiac adverse events, vs ibrutinib in a randomized,head-to-head study of patients with CLL/SLL (Brown et al. N/A

P1/2, N=70, Active, not recruiting, Iovance Biotherapeutics, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jul 2024 --> Sep 2025 | Trial primary completion date: Apr 2024 --> Sep 2025

Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

P=N/A, N=193, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | N=315 --> 193

The first-line treatment with IB is absolutely cost-effective compared to the first-line BE plus RI treatment strategy for 65 or older patients with CLL without the del (17p)/TP53 mutation from the Chinese payer perspective. Therefore, it is strongly recommended that Chinese health authorities select the former strategy for these CLL patients.

88 patients were identified, 85 had a diffuse large lymphoma histology and 3 Hodgkin's lymphoma. The median age was 61 years (range 25-74), and the majority (n=61, 69%) of patients were in complete response (CR, N=21) or partial response (PR, N=40) pre-SCT. Median follow-up among survivors was 74 months (range: 8-168); all outcomes are reported at 6 years.

In this Belgian real-world study, ibrutinib was found to be an effective treatment for patients with CLL, including those with higher risk mutations, several prior LOTs, and older age, with first-line patients who joined the study later responding particularly well. These findings are consistent with those from clinical trials, which support more effective outcomes for ibrutinib when utilized in the frontline (eg, RESONATE-2: Barr PM, et al. Blood Adv.

Introduction: Venetoclax in combination with rituximab (VenR) along with either ibrutinib or acalabrutinib monotherapy represent the most common regimens currently used for the treatment of relapsed/refractory (RR) chronic lymphocytic leukemia (CLL) in the Czech Republic...Bendamustine and rituximab followed by fludarabine, cyclophosphamide and rituximab were the most common regimens used in the firs-line treatment... In terms of high-risk prognostic markers, a higher prevalence of del 17p and/or TP53 mutation, and del 11q were observed in the BTKi cohort. In contrast, frequency of the unmutated IGVH gene was comparable in both groups. Difference in median PFS and OS was not statistically significant within the current follow-up period.

Background: A phase II trial has shown, first-line treatment with iFCG (ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab) led to a bone marrow (BM) undetectable minimal residual disease (uMRD) rate of 98% (44/45) as best response in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL). This is the first clinical trial exploring the efficacy and safety of the second generation BTKi plus chemoimmunotherapy in patients with CLL. The OFCG regimen shows a rapid and deep molecular remission with a pleasant safety profile in the TN CLL patients including the ones with unfavorable factors.

Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.

5 pts have started subsequent therapy (acalabrutinib, n=4; ibrutinib, n=1; all are clinically responding); 1 pt has not yet started therapy. We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 5-year PFS of 90.1%. The 5-year PFS for pts with del(17p)/TP53 mutation is 86.1%. Retreatment with BTK inhibitor appears effective for pts with disease relapse.

There was considerable discordance between HCP and expert treatment choices for various case scenarios in multiple educational activities; for example, for patient cases without del(17p)/TP53-mutated/IGHV-mutated CLL and bulky disease with diminished creatinine clearance, experts would recommend acalabrutinib with or without obinutuzumab for 77% of scenarios, while HCPs selected this treatment 35% of the time (Table)...One half of responding HCPs (52%) were able to identify characteristics that would qualify a patient for inpatient administration of the initial doses of venetoclax because of increased risk of tumor lysis syndrome (n = 48). Finally, among 213 HCPs participating in educational activities from September 2022 to June 2023, 43% were aware of recent data regarding the use of pirtobrutinib, an investigational noncovalent BTK inhibitor, for treating patients with CLL... Our data suggest that many HCPs are challenged to optimally incorporate contemporary treatment recommendations into the care of patients with CLL and struggle to maintain knowledge of investigational therapies that may affect the treatment landscape in the near future. Continuing educational activities designed to improve the knowledge, competence, and confidence of HCPs in the care of CLL would benefit patients with this disease. A more detailed data analysis of treatment trends and knowledge by geographic location and role on the care team will be presented.

Background Patients (pts) with IGHV-mutated (IGHV-M) CLL have favorable long-term outcomes after receiving first-line FCR (fludarabine, cyclophosphamide and rituximab)...Two pts had clinical progression: one pt had IGHV 3-21; MRD recurred 28 mos after discontinuing ibrutinib, with clinical relapse 59 mos after discontinuing ibrutinib; this pt is now in remission with venetoclax-based therapy; the second pt with clinical relapse had IGHV-unmutated CLL, MRD recurred 24 mos after discontinuing ibrutinib, with clinical relapse 48 mos after discontinuing ibrutinib; this pt has not yet required therapy for relapse...Additionally, these results also appear favorable to the current targeted therapy regimens (such as BTKi, BCL2i+CD20 antibody) for IGHV-M CLL. With the caveat that the role of chemoimmunotherapy in CLL has significantly declined, the iFCG regimen provides for a very high rate of durable remissions among a chemo-sensitive subgroup of pts with CLL.

Among the 160 patients with symptomatic or progressive lymphadenopathy/splenomegaly or extranodal disease, the treatments administered include: mAb alone (n=35), chemotherapy alone (n=33), chemoimmunotherapy (n=57), targeted agent (n=33; Bruton tyrosine kinase inhibitor [BTKi] based n=28; venetoclax-based n=3, BTKi + venetoclax n=2), and other (n=2)...Trisomy 12 was the most frequently detected abnormality on peripheral blood FISH testing. Treatment with novel agents achieved durable TFS and OS.

To our knowledge, this is the largest real-world study examining treatment-naive elderly patients receiving ibrutinib as first-line therapy. Ibrutinib represents a suitable therapeutic choice even for patients aged >80 years with comorbidities. In this setting of patients, the drug was well tolerated and no new side effects were recorded.

This may be increasingly possible in the era of monoclonal antibodies and T cell redirection therapies. Analysis of larger real-world MM cohorts is needed to elucidate whether sustained MRD-negative remission at 5 years can truly predict long-term disease-free survival and possible cure.

Conclusions The time-limited MRD-guided triple combination of zanu, ven and obi induced deep remissions in a r/r CLL population enriched for pts previously treated with BTKi and/or ven. Apart from COVID-19, low rates of infectious AEs were observed and cardiac toxicities were rare.

Currently, ven is FDA approved as either monotherapy (mono) or in combination (combo) with rituximab (R) In patients with relapsed/refractory (R/R) CLL (Seymour et al...Ven based treatment consisted of ven mono or in combo with R, obinutuzumab (G), or ibrutinib (BTKi) with standard ven dose ramp up to a maximum dose of 400mg daily... In a high-risk population of pts with R/R CLL, we found that ven based tx leads to durable remissions, with high rates of uMRD. Combo approaches with the addition of either an anti-CD20mab or BTKi led to improved PFS. While venR is the current FDA approved combo regimen for pts with R/R CLL, we found that there was a trend for improved PFS with either venG or ven + BTKi compared to ven mono.

Whereas fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy (CIT) had a median progression-free survival (mPFS) of 11.2 months and median overall survival (mOS) of 33.1 months as frontline therapy in del17p CLL (Fisher et al...In a similar patient subset, the CLL14 study demonstrated a mPFS of 51.9 months and a 5-year OS of 60.0% using fixed-duration venetoclax and obinutuzumab (Al-Sawaf et al... These results further define the long-term prognosis of patients treated with BTK inhibitors for CLL, most notably with substantial improvements in the OS of patients with TP53 alterations over CIT. Additionally, these results may inform discussions of continuous BTK inhibitor therapy versus fixed-duration venetoclax combinations in frontline therapy of high-risk CLL. In a subset of ibrutinib-treated patients, depth of response increased over multiple years to the point of uMRD suggesting the possibility that such patients might safely discontinue therapy, following paradigms established in patients with chronic myelogenous leukemia.

ALPINE was the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors. At a median follow-up of 3 years, the study showed sustained PFS benefits of zanubrutinib over ibrutinib. The durable PFS benefits with zanubrutinib were observed across major subgroups, including multiple sensitivity analyses.

Our real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2.

Here we present first real world data demonstrating Ven to be an effective MM treatment option in heavily pretreated MM patients.

Three months after initiation of belamaf, the pt had progressive disease and teclistamab was initiated, but failed to induce another response. BCMA-directed treatment, especially CAR-T cell treatment, opens a new therapeutic era in RRMM. So far, limited data exist on mechanisms of resistance. Here, we report genetic alterations in the TNFRSF17 gene in 2 pts with underlying HR disease and early and atypical relapse after CAR-T treatment.

An improved understanding of the disease biology has contributed to the development of novel agents able to target key pathways in CLL.2 Two classes of targeted agents have been extremely impactful in shaping current treatment of CLL: the BCL2 inhibitor venetoclax and the Bruton's tyrosine kinase inhibitors (BTKi) ibrutinib, acalabrutinib and zanubrutinib...Patients received six 28-day cycles of ibrutinib in combination with fludarabine, cyclophosphamide and rituximab (FCR) followed by 2 years of ibrutinib maintenance...The combination of ibrutinib-venetoclax demonstrated superior progression-free survival (24 months estimated rate 84.4% for patients treated with ibrutinib-venetoclax and 44.1% for patients treated with chlorambucil-obinutuzumab) and superior rates of U-MRD (55.7% vs 21%).15 The time-limited approach with concomitant administration of BTK and BCL2 targeting agents has potential advantages over continuous BTK inhibitor-based therapy in terms of reduced risk for treatment-related side effects due to the prolonged administration and potentially lower costs8 , however, there are still open questions in terms of selection of therapy at time of retreatment and quality and durability of responses to subsequent therapies. It is important to note that treatment with combination of BTKi and venetoclax with or without CD20 monoclonal antibodies is not FDA approved and is still being investigated in clinical trials.

P=N/A, N=315, Recruiting, AstraZeneca

Introduction: Targeted agents, such as covalent BTKi- (cBTKi; i.e. acalabrutinib, ibrutinib, zanubrutinib) and BCL2i- based regimens (i.e. venetoclax), have demonstrated improved treatment efficacy and safety compared to CT/CIT for patients with CLL/SLL. Patients who switched to a BCL2i-based regimen were more likely to respond to therapy and had lower hazard of progression/death; TTNT-D results also suggested a possible benefit of BCL2i over cBTKi. Switching to BCL2i-based regimens post-cBTKi demonstrates better treatment outcomes compared to cycling through consecutive cBTKis, further highlighting the effectiveness of BCL2i in real-world settings. Given the dynamic treatment landscape in CLL, the impact of switching to agent(s) with a different MOA or choosing to retreat with agent(s) in the same class are key considerations in optimizing clinical care.

Zilo + Ibr is well-tolerated with a safety profile that is comparable to Ibr alone. For pts with CLL, Zilo + Ibr is very active and results in durable remissions. The PFS and OS for the subgroup with TP53 mut/del(17p) are particularly encouraging in reference to other trials of BTK inhibitors, maintaining 100% PFS and OS at ∼42 mos.

In the CLL14 study, symptomatic patients with CLL receiving frontline therapy with VO had longer progression-free survival (PFS) and deeper remissions [more undetectable minimal residual disease (MRDu)] compared with to that seen in patients receiving chlorambucil and obinutuzumab [1]. Current status: At the time of submission, 67 patients have been registered and randomized per protocol. Accrual is ongoing.

Under real-world conditions, Ven monotherapy is used in heavily pre-treated elderly patients. The treatment was well tolerated. TLS monitoring deviated from recommended lab monitoring procedures as specified in the Ven label.

The rate of uMRD increased with the continued maintenance with the GAVe triple combination and 25 pts (58%) stopped maintenance due to achievement of a deep remission with uMRD. Randomized trials will define if the triple combination of a BTK inhibitor, a BCL2 inhibitor and a CD20 antibody is superior to combinations of two of these agents. Until then, the use of this triple combination in routine practice cannot be recommended.

Thirty-six-month overall survival (OS) rates were >95% regardless of high-risk features. Deep, durable responses and sustained PFS seen with fixed-duration ibrutinib plus venetoclax are maintained in patients with high-risk genomic features, with similar PFS and OS to those without high-risk features.

They are also generally well tolerated, with the newer BTK inhibitors demonstrating better tolerability than ibrutinib while maintaining efficacy. BTK inhibitors after venetoclax may be effective, but long-term data is limited. Given these reasons, BTK inhibitors remain the preferred treatment option as initial therapy for patients with CLL, especially those with del17p or TP53 mutations.

P=N/A, N=350, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting

Several targeted treatments, such as venetoclax + obinutuzumab (VenO) and ibrutinib, have emerged to treat treatment-naïve patients with chronic lymphocytic leukemia (CLL) and have been shown to improve progression-free survival (PFS) compared to chlorambucil + obinutuzumab (ClbO)...VenO, ClbO, or ibrutinib was included as first-line therapy followed by either Ven plus rituximab or ibrutinib...The ICER was €302,156/QALY, indicating that ibrutinib in first-line treatment would not be considered cost-effective in Danish healthcare compared to VenO. Future analyses in fit patients with CLL patients are needed to determine the cost-effectiveness of VenO.

Among the 29 patients in ≥L2, previous therapies included bendamustine and rituximab (36.0%), fludarabine, cyclophosphamide, rituximab (FCR, 32.0%), ibrutinib (20.0%), chlorambucil and rituximab (16.0%) or chlorambucil (20.0%). L1 patients received acalabrutinib monotherapy (61.0%) and as combination (39.0%), mostly with obinutuzumab... The NAOS study is one of the first real-life descriptions of patients receiving acalabrutinib in Europe. In this first analysis, most patients received acalabrutinib as first-line therapy. Acalabrutinib was used in patients older than in the published phase III clinical trials, with more frailties (ECOG, creatinine clearance) and cardiovascular risks.

Racial disparities were observed in clinical characteristics, comorbidity burden, and type of therapy at the time of treatment initiation for 1L CLL, resulting in a large disadvantage in the median PFS for Black pts in the yearsimmediately following the advent of targeted agents. However, after weighting, this difference in the median PFS was attenuated relative to White pts. These data suggest that access to adequate care with more effective targeted treatments may help reduce racial disparities for pts in real-world settings, as well as reducing their comorbidity burden.

Our preliminary data indicate that combination of acalabrutinib and obinutuzumab induces remissions with significant reduction in bone marrow disease. Longer treatment and follow-up are warranted to determine the durability of responses after therapy discontinuation. Figure: Bone marrow MRD levels during treatment with acalabrutinib and obinutuzumab.