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BIOMARKER:

TP53 mutation + Chr del(17p)

i
Other names: TP53, Tumor Protein P53, Cellular Tumor Antigen P53, Phosphoprotein P53, Tumor Protein P53, Antigen NY-CO-13, Transformation-Related Protein 53, Mutant Tumor Protein 53, P53 Tumor Suppressor, Tumor Suppressor P53, Tumor Protein 53, BMFS5, TRP53, BCC7, LFS1
Entrez ID:
2ms
Sustained Benefit of Zanubrutinib vs Ibrutinib in Patients With R/R CLL/SLL: Final Comparative Analysis of ALPINE. (PubMed, Blood)
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.
Journal
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Imbruvica (ibrutinib) • Brukinsa (zanubrutinib)
2ms
CELESTIAL-TNCLL: AN ONGOING, OPEN-LABEL, MULTIREGIONAL, PHASE 3 STUDY OF SONROTOCLAX (BGB-11417) + ZANUBRUTINIB VS VENETOCLAX + OBINUTUZUMAB IN TREATMENT-NAIVE CLL (SIE 2024)
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.
P3 data • Clinical • IO biomarker
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 mutation + Chr del(17p)
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clonoSEQ
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Gazyva (obinutuzumab) • Brukinsa (zanubrutinib) • sonrotoclax (BGB-11417)
6ms
COMBINED PIRTOBRUTINIB, VENETOCLAX, AND OBINUTUZUMAB IN FIRST-LINE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A PHASE 2 TRIAL (EHA 2024)
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.
P2 data • Clinical
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TP53 (Tumor protein P53)
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TP53 mutation • KRAS mutation • NOTCH1 mutation • Chr del(11q) • SF3B1 mutation • TP53 mutation + Chr del(17p) • Chr del(17p) + Chr del(11q) • TS 12
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clonoSEQ
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Gazyva (obinutuzumab) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Jaypirca (pirtobrutinib)
6ms
CELESTIAL-TNCLL: AN ONGOING, OPEN-LABEL, MULTIREGIONAL, PHASE 3 STUDY OF SONROTOCLAX (BGB-11417) + ZANUBRUTINIB VS VENETOCLAX + OBINUTUZUMAB FOR TREATMENT-NAIVE (TN) CLL (EHA 2024)
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
P3 data • Clinical • IO biomarker
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 mutation + Chr del(17p)
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clonoSEQ
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Gazyva (obinutuzumab) • Brukinsa (zanubrutinib) • sonrotoclax (BGB-11417)
6ms
IOV-CLL-01: Study of Autologous Peripheral Blood Lymphocytes in the Treatment of Patients With CLL or SLL (clinicaltrials.gov)
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
Enrollment closed • Trial completion date • Trial primary completion date
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TP53 (Tumor protein P53) • IL2 (Interleukin 2)
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TP53 mutation • TP53 mutation + Chr del(17p)
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IOV-2001
7ms
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024. (PubMed, J Natl Compr Canc Netw)
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.
Journal • IO biomarker
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p) • IGH mutation
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Venclexta (venetoclax)
8ms
PICAROS - Acalabrutinib RWE on 1L CLL in Spain (clinicaltrials.gov)
P=N/A, N=193, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | N=315 --> 193
Enrollment closed • Enrollment change • Real-world evidence • Real-world
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation + Chr del(17p)
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Calquence (acalabrutinib)
11ms
Ibrutinib versus bendamustine plus rituximab for first-line treatment of 65 or older patients with untreated chronic lymphocytic leukemia without del(17p)/TP53 mutation in China: a lifetime economic research study. (PubMed, BMC Health Serv Res)
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.
Journal
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Imbruvica (ibrutinib) • Rituxan (rituximab) • bendamustine
12ms
Allogeneic Transplant for CLL Richter's Transformation: Single Center Retrospective Analysis (ASH 2023)
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.
Retrospective data
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 mutation + Chr del(17p)
12ms
Second Line Treatment with Bruton Tyrosine Kinase Inhibitor (BTKi) or Bcl-2 Inhibitor (Bcl-2i) in Patients with Chronic Lymphocytic Leukemia (CLL): Primary Analysis of the Czech Study Group for CLL (CSCLL) (ASH 2023)
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.
Clinical • IO biomarker
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TP53 (Tumor protein P53)
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TP53 mutation • Chr del(11q) • TP53 mutation + Chr del(17p)
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • cyclophosphamide • Calquence (acalabrutinib) • bendamustine • fludarabine IV
12ms
Real-World Effectiveness and Safety of Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) in Belgium after 4 Years (ASH 2023)
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.
Clinical • Real-world evidence • Real-world effectiveness • Real-world
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p) • IGH mutation
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Imbruvica (ibrutinib)
1year
Orelabrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (OFCG) for First-Line Treatment of Chronic Lymphocytic Leukemia: A Multicenter, Investigator-Initiated Study (cwCLL-001 Study) (ASH 2023)
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.
Clinical • IO biomarker
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • Chr del(11q) • TP53 mutation + Chr del(17p) • IGH mutation • Chr del(17p) + Chr del(11q)
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Imbruvica (ibrutinib) • Gazyva (obinutuzumab) • cyclophosphamide • Yinuokai (orelabrutinib) • fludarabine IV
1year
Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 5-Year Follow-up Data (ASH 2023)
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.
Clinical • IO biomarker
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • Chr del(11q) • TP53 mutation + Chr del(17p) • BCL2 mutation
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Calquence (acalabrutinib)
1year
First Results from a Phase 1, First-in-Human Study of the Bruton's Tyrosine Kinase (BTK) Degrader Bgb-16673 in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Malignancies (BGB-16673-101) (ASH 2023)
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.
Clinical • P1 data • IO biomarker
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TP53 (Tumor protein P53) • BTK (Bruton Tyrosine Kinase) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p) • BTK mutation
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BGB-16673
1year
Determining Clinical Practice Gaps for HCPs in Treating CLL Using CME-Based Surveys (ASH 2023)
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.
Clinical
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • TP53 mutation + Chr del(17p) • IGH mutation
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Venclexta (venetoclax) • Gazyva (obinutuzumab) • Calquence (acalabrutinib) • Jaypirca (pirtobrutinib)
1year
Outcomes of Patients with Small Lymphocytic Lymphoma (SLL) Receiving First Line Treatment (ASH 2023)
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.
Clinical • IO biomarker
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • Chr del(11q) • TP53 mutation + Chr del(17p) • TS 12
|
Venclexta (venetoclax)
1year
Ibrutinib, Fludarabine, Cyclophosphamide and Obinutuzumab (iFCG) for Firstline Treatment of Patients with CLL with Mutated IGHV and without Del(17p)/TP53 Mutation: Six-Year Follow-up Analyses (ASH 2023)
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.
Clinical • IO biomarker
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • TP53 mutation + Chr del(17p) • IGH mutation
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Gazyva (obinutuzumab) • cyclophosphamide • fludarabine IV
1year
Ibrutinib As First Line Therapy in Chronic Lymphocytic Leukemia Patients over 80 Years Old: A Retrospective Real-Life Multicenter Italian Cohort (ASH 2023)
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.
Retrospective data
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • TP53 mutation + Chr del(17p) • IGH mutation
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Imbruvica (ibrutinib)
1year
MRD-Guided Zanubrutinib, Venetoclax and Obinutuzumab after an Optional Debulking with Bendamustine in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Primary Endpoint Analysis of the Phase 2 CLL2-Bzag Study (ASH 2023)
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.
Clinical • P2 data • IO biomarker
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p)
|
Venclexta (venetoclax) • Gazyva (obinutuzumab) • Brukinsa (zanubrutinib) • bendamustine
1year
Comparison of Venetoclax Based Treatments for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (ASH 2023)
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.
Clinical • IO biomarker
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • Chr del(11q) • TP53 mutation + Chr del(17p) • IGH mutation • TS 12
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Gazyva (obinutuzumab)
1year
Durable MRD and Imaging-Negative Remission ≥ 5 Years Post-Therapy Predicts Long-Term Progression-Free Survival in Multiple Myeloma Patients – a Single-Center Observational Study (ASH 2023)
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.
Clinical • Observational data
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 mutation + Chr del(17p)
1year
Extended Follow-up of ALPINE Randomized Phase 3 Study Confirms Sustained Superior Progression-Free Survival of Zanubrutinib Versus Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL) (ASH 2023)
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.
Clinical • P3 data
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 mutation + Chr del(17p)
|
Imbruvica (ibrutinib) • Brukinsa (zanubrutinib)
1year
Long-Term Outcomes in Chronic Lymphocytic Leukemia Treated with Ibrutinib: 10-Year Follow-up of a Phase 2 Study (ASH 2023)
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.
P2 data • IO biomarker
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • TP53 mutation + Chr del(17p)
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Gazyva (obinutuzumab) • cyclophosphamide • fludarabine IV
1year
Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia: A Swedish nation-wide real-world report on consecutively identified patients. (PubMed, Eur J Haematol)
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.
Journal • Real-world evidence • IO biomarker • Real-world
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
|
TP53 mutation • TP53 mutation + Chr del(17p)
|
Rituxan (rituximab) • Zydelig (idelalisib)
1year
Venetoclax Salvage Therapy in Relapsed/Refractory Multiple Myeloma (DGHO 2023)
Here we present first real world data demonstrating Ven to be an effective MM treatment option in heavily pretreated MM patients.
IO biomarker
|
TP53 (Tumor protein P53)
|
TP53 mutation • Chr t(11;14) • TP53 mutation + Chr del(17p) • Chr t(4;14) • Chr t(14;16) • BCL2 expression
|
Venclexta (venetoclax)
1year
Real-world experiences with detection of secondary resistance mechanisms against BCMA-targeting therapies by Whole Genome Sequencing and its association with clinical course in Multiple Myeloma patients (DGHO 2023)
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.
Clinical • Real-world evidence • IO biomarker • Real-world • Whole genome sequencing
|
TP53 (Tumor protein P53) • TNFRSF17 (TNF Receptor Superfamily Member 17)
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TP53 mutation • TP53 mutation + Chr del(17p) • TNFRSF17 expression
|
Blenrep (belantamab mafodotin-blmf) • Tecvayli (teclistamab-cqyv)
1year
Is Fixed-Duration Therapy the New Standard of Care in Frontline CLL? (SOHO 2023)
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.
IO biomarker
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • Chr del(11q) • TP53 mutation + Chr del(17p) • IGH mutation
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Gazyva (obinutuzumab) • cyclophosphamide • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Leukeran (chlorambucil) • fludarabine IV
1year
New trial • Real-world evidence • Real-world
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation + Chr del(17p)
|
Calquence (acalabrutinib)
over1year
Phase 1/2 Study of Zilovertamab and Ibrutinib: Durable responses suggest a novel mechanism for synthetic lethality in TP53 aberrant disease. (IWCLL 2023)
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.
P1/2 data • Synthetic lethality
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TP53 (Tumor protein P53) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • NFE2L2 (Nuclear Factor, Erythroid 2 Like 2)
|
TP53 mutation • TP53 mutation + Chr del(17p)
|
Imbruvica (ibrutinib) • zilovertamab (UC-961)
over1year
SWITCHING FROM COVALENT BTKI TO BCL2i IS ASSOCIATED WITH IMPROVED CLINICAL OUTCOMES COMPARED TO SWITCHING TO A DIFFERENT COVALENT BTKI IN PATIENTS WITH CLL/SLL TREATED IN THE REAL-WORLD SETTING (IWCLL 2023)
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.
Clinical • Clinical data • Real-world evidence • Real-world
|
TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
|
TP53 mutation • LDH elevation • TP53 mutation + Chr del(17p)
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib)
over1year
Randomized, Phase III Study of Early Intervention with Venetoclax and Obinutuzumab (VO) versus Delayed Therapy with VO in Newly Diagnosed Asymptomatic High-Risk Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): EVOLVE CLL/SLL Study (SWOG S1925; NCT#04269902) (IWCLL 2023)
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.
Clinical • P3 data • IO biomarker
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Venclexta (venetoclax) • Gazyva (obinutuzumab) • Leukeran (chlorambucil)
over1year
SAFETY AND EFFECTIVENESS IN CLL PATIENTS TREATED WITH VENETOCLAX MONOTHERAPY IN AUSTRIA, GERMANY, AND SWITZERLAND - LONG TERM FOLLOW UP DATA (IWCLL 2023)
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.
Clinical • IO biomarker
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IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Venclexta (venetoclax)
over1year
Bendamustine, Followed by Obinutuzumab, Acalabrutinib and Venetoclax in Patients (Pts) with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL): Updated Results of the CLL2-BAAG Trial of the German CLL Study Group (GCLLSG) (IWCLL 2023)
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.
Clinical • IO biomarker
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Venclexta (venetoclax) • Gazyva (obinutuzumab) • Calquence (acalabrutinib) • bendamustine
over1year
Outcomes in Patients with High-Risk Features after Fixed-Duration Ibrutinib plus Venetoclax: Phase II CAPTIVATE Study in First-Line Chronic Lymphocytic Leukemia. (PubMed, Clin Cancer Res)
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.
P2 data • Journal
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p) • IGH mutation
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Venclexta (venetoclax) • Imbruvica (ibrutinib)
over1year
Cross Fire: BTK Inhibitors Alone or in Combination are the Best Frontline Therapy for CLL. (PubMed, Hematol Oncol Stem Cell Ther)
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.
Journal
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Venclexta (venetoclax) • Imbruvica (ibrutinib)
over1year
Enrollment closed
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TP53 (Tumor protein P53)
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TP53 mutation • Chr del(17p) • TP53 mutation + Chr del(17p)
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Venclexta (venetoclax)
over1year
Cost-effectiveness of targeted treatment vs chemoimmunotherapy in treatment-naïve unfit CLL without TP53 aberrations. (PubMed, Blood Adv)
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.
Journal • HEOR • IO biomarker • Cost-effectiveness • Cost effectiveness
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TP53 (Tumor protein P53)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Gazyva (obinutuzumab) • Leukeran (chlorambucil)
over1year
NAOS STUDY: FIRST INTERIM ANALYSIS OF ACALABRUTINIB USE IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IN A REAL-LIFE SETTING. (EHA 2023)
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.
Clinical • IO biomarker
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TP53 (Tumor protein P53)
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TP53 mutation • Chr del(17p) • Chr del(11q) • TP53 mutation + Chr del(17p)
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Imbruvica (ibrutinib) • Rituxan (rituximab) • Gazyva (obinutuzumab) • cyclophosphamide • Calquence (acalabrutinib) • bendamustine • Leukeran (chlorambucil) • fludarabine IV
over1year
RACIAL DISPARITIES IN REAL-WORLD TREATMENT PATTERNS AND OUTCOMES AMONG PATIENTS WITH CLL (EHA 2023)
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.
Clinical • HEOR • Real-world evidence • Real-world
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TP53 (Tumor protein P53) • NOTCH1 (Notch 1) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • ATM mutation • TP53 mutation + Chr del(17p)
over1year
LONG-TERM OUTCOMES WITH CONTINUOUS IBRUTINIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: ANALYSIS OF TIME TO PROGRESSION (EHA 2023)
Overall, 13% of previously untreated patients with CLL had PD with ibrutinib-based standard-of-care treatment at a median 42 months of follow-up. Only 7% of patients who remained on active ibrutinib treatment experienced PD, and the likelihood of remaining progression free at 8 years was 78%. No new safety signals were identified in published results of the respective studies.
Clinical
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Imbruvica (ibrutinib)
over1year
TRACKING DISEASE PARAMETERS BY MRD, CT AND PET IN FIRST LINE CLL PATIENTS TREATED WITH FIXED DURATION IBRUTINIB-VENETOCLAX; INTERIM ANALYSIS OF THE FIRST 30 PATIENTS IN HOVON 158/NEXT STEP TRIAL. (EHA 2023)
Background: HOVON 158/NEXT STEP trial is a phase 2 study in patients with previously untreated chronic lymphocytic leukemia (CLL), evaluating the efficacy and safety of adding 6 cycles of ibrutinib-obinutuzumab to patients who are not in complete remission (CR) and/or have minimal residual disease (MRD) after fixed-duration ibrutinib- venetoclax (IV). Fixed-duration IV is an effective and safe treatment combination, although dose reductions are common. Detailing responses by CT reveal kinetics of CLL clearance, with faster normalisation of spleen and liver than LN. PET provides additional information on activity of residual CLL sites.
Clinical
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Gazyva (obinutuzumab)
over1year
TIME-LIMITED TREATMENT WITH ACALABRUTINIB PLUS OBINUTUZUMAB IN TREATMENT-NAÏVE CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS: EARLY RESULTS OF AN ONGOING PHASE 2 TRIAL (EHA 2023)
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.
Clinical • P2 data
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus) • B2M (Beta-2-microglobulin)
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TP53 mutation • TP53 mutation + Chr del(17p)
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Gazyva (obinutuzumab) • Calquence (acalabrutinib)