Chr del(17p)

We performed a retrospective analysis of 130 patients with CLL with baseline del(17p) and/or TP53-m treated with BTKi with or without the BCL2 inhibitor venetoclax (VEN) and with or without CD20 antibody in the firstline setting...Del(17p) was identified in <25% of cells in 26/104 (25%) of patients, and 28/101 (28%) of TP53-m were low-burden with a VAF of <10%; outcomes of these patients were similar to those with high-burden lesions. This study suggests that low-burden TP53 alterations should not be ignored when assessing genomic risk in CLL in the era of targeted therapy.

At the same time, the occurrence of “hot spots” mutations in MCL and FL is also higher than expected. Further studies concerning the type of mutations, their allelic load, and their combination with 17th chromosome lesions in association with disease course are on the way.

Drugs that interfere with these pathways, such as ibrutinib, venetoclax, and idelalisib, have improved clinical outcomes. Nevertheless, patients without high-risk features such as TP53 abnormalities also benefit from novel agents. Following relapse, depending on the primary oral agent used, BTK inhibitors, venetoclax in combination with anti-CD20 antibodies, or PI3K inhibitors are preferred.

P=N/A, N=350, Recruiting, AbbVie | Trial completion date: Dec 2025 --> Dec 2024 | Trial primary completion date: Dec 2025 --> Dec 2024

P=N/A, N=350, Recruiting, AbbVie | N=59 --> 350 | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=27, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2021 --> Dec 2022

P2, N=0, Withdrawn, M.D. Anderson Cancer Center | N=20 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=20, Active, not recruiting, Ciusss de L'Est de l'Île de Montréal | Recruiting --> Active, not recruiting

In addition, ∼40% of CLL cases bearing T12, 17p, and 11q showed unidentified microdeletions of miR-15a/16-1, suggesting that miR-15a/16-1 loss cooperates with such chromosomal alterations in CLL. These data may have clinical relevance for the successful stratification of patients for treatment.

Notably, the acquisition of TP53 alterations at relapse dramatically worsened the clinical course of patients. Overall, our analyses showed these techniques to be highly sensitive to identify TP53 aberrations at sub-clonal level, emphasizing the poor prognosis associated with double-hit MM patients.

P1b, N=48, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=15, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2022 --> May 2023 | Trial primary completion date: May 2022 --> May 2023

P1/2, N=20, Recruiting, Ciusss de L'Est de l'Île de Montréal | Trial completion date: Mar 2024 --> Sep 2025 | Trial primary completion date: Mar 2022 --> Sep 2021

P1b, N=48, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

When treatment is indicated, several therapeutic options exist: a combination of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax with obinutuzumab, monotherapy with inhibitors of Bruton tyrosine kinase (BTK) such as ibrutinib and acalabrutinib, or chemoimmunotherapy. Moreover, the optimal sequencing of targeted therapies remains to be determined. A particular challenge of the next few years will be to identify alternative therapies for patients with BTK and BCL2 inhibitor double-refractory disease.

P=N/A, N=59, Recruiting, AbbVie | Trial completion date: Dec 2025 --> Dec 2024 | Trial primary completion date: Dec 2025 --> Dec 2024

P=N/A, N=59, Recruiting, AbbVie | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P3b, N=553, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P1, N=30, Active, not recruiting, Noah Merin | Recruiting --> Active, not recruiting

Here we show a high sensitivity, specificity, and NPV when comparing targeted sequencing with FISH. FISH panel testing is widely used in clinical practice to characterize highly prognostic chromosomal abnormalities in CLL. Comprehensive genetic profiling with NGS has become increasingly important in the work up of hematologic malignancies and provides additional prognostic and predictive information, including clinically relevant mutations such as TP53, SF3B1 , and NOTCH1, tumor mutation load and mutations associated with resistance to chemo-immunotherapy and targeted therapies, such as BTK or BCL2 inhibitors, that FISH cannot offer.

The presence of i(17q) retained independent poor prognostic value in multivariable Cox-regression analysis &lsqb;HR 3.686 (1.17-11.6); P = 0.026] along with splenomegaly. We suggest that MDS/MPN-i(17q) warrants recognition as a distinct subtype within the MDS/MPN-U category based on its unique clinico-biologic features and uniformly poor prognosis.

Presence of complex cytogenetics and not bridging into allo-HSCT are two factors affecting the long-term efficacy. Further studies are needed to confirm these results, to improve the clinical management and personalization of treatment approaches for B-ALL patients harboring TP53 mutation/chromosome 17p deletion.

This analysis provides the current state of 1L CLL testing and treatment patterns and outcomes in the US from 2015 to 2020. As expected, the use of novel targeted oral agents increased over time, with a corresponding increase in TTNTD. Clinical outcomes were improved in patients receiving novel targeted oral agents, both overall and in high-risk subgroups.

Regarding novel targeted agents, 1860/9173 (20.2%) patients had received at least one line of treatment with BTKi (ibrutinib, n=1788; acalabrutinib, n=72) over the disease course; 631/9173 (6.9%) with venetoclax; and, 447/9173 (4.9%) with the PI3K inhibitor idelalisib...The great majority (865/1086 cases, 79.7%) of patients who received a second line before 2014 were retreated with CIT, most commonly Bendamustine-Rituximab (284/1086, 26.1%) and Fludarabine-Cyclophosphamide-Rituximab (252/1086, 23.2%); alemtuzumab monotherapy was used in 55/1086 (5%) of patients...Patients treated with CIT (n=694) had an ORR of 68.7% (28.3% CR+40.4% PR). In conclusion, in a large international study we provide real world data regarding the selection and sequencing of treatment in CLL, charting a major shift in treatment patterns before and after the Introduction of novel trargeted agents and confirming their efficacy even in high-risk CLL.

In a patient in complete response (CR) after 5 cycles RVD (Lenalidomide, Bortezomib, Dexamethasone), autologous stem cell transplant (ASCT) and 5 years of lenalidomide maintenance, follow-up PET/CT showed a single new FL in the caudal right ilium. Our findings showing divergent results from MRD assessments in bone marrow and FL underline the critical role of whole-body imaging for follow-up of patients in remission. Sampling plasma cells solely from the IC limits the ability for complete clinical decision-making.

Additional cytogenetic testing demonstrates alternative genetic alterations are common in normal 12/13/11/17 CLL pts, however, our data do not show that these alterations are significant independent predictors of TTFT or OS. While normal FISH CLL is a relatively heterogeneous group, pts with mutated IGHV represent a subset of pts with very low risk disease.

Our results also highlight that BCMA expressions in bulk sample may not detect the presence or absence of cells with target loss and therefore combining strategies at bulk and single cell level are necessary to understand the disease status. These results suggest the need to study del16p in patients being targeted for BCMA-directed therapy and its association with other risk factors in MM.

Preliminary safety data with the 9.7-mo median follow-up suggest that zanubrutinib + venetoclax was generally well tolerated in this high-risk population, with no new safety signals identified and no TLS reported. Enrollment is ongoing; updated safety, efficacy, and biomarker data will be presented.

Introduction The search for somatic hypermutation of the IGHV gene, together with karyotype analysis and fluorescence in situ hybridization (FISH), are valuable resources for the prognostic stratification in chronic lymphocytic leukemia (CLL). About 80% of CLL cases have genetic alterations that correlate with prognosis.Objective To correlate alterations detected by karyotype and FISH in patients not mutated to the IGHV gene and to evaluate the importance of combining these findings.Methodology Thirty blood samples were analyzed peripheral or bone marrow of patients with CLL. Molecular testing for IGHV was performed by reverse transcription and amplification of the mRNA corresponding to the IGHV gene, followed by sequencing and database comparison. Karyotyping was performed by means of culture stimulated with mitogens B and/or oligo, and FISH used probes for MY B, cen12, IGH, RB1, ATM and TP53. Result 7 (23.33%) patients had complex karyotype ( ≥3 changes) and abnormal FISH that complemented each other; 7 (23.33%) patients had trisomy 12 in both tests; 5 (16.67%) demonstrated a normal karyotype with altered FISH (deletion of the MYB, TP53 and trisomy 12 genes). In 1 (3.33%) the 17p deletion was detected simultaneously in both tests; 1 (3.33%) had a rearrangement involving the long arm of chromosome 17; 4 (13.33%) had alterations involving one of the chromosomes: 4, 6, 11, 13 and 14 and one of the genes: MYB, ATM, RB1 and IGH. In 5 cases (16.67%), it was not possible to obtain viable metaphases in the karyotype, however FISH detected alterations involving one of the genes: ATM, RB1, IGH, TP53 and trisomy of chromosome 12.Conclusion Karyotype, FISH and IGHV carried out, simultaneously, showed relevant data for the prognostic stratification of patients with CLL. More than 50% of the detected alterations, both those found in the karyotype, such as cases with complex karyotype, and other alterations considered only in FISH, corroborated the literature, showing that they are equally unfavorable and of aggressive course, as is the case with presence of the non-mutated IGHV gene.

These same factors as well as IPSSWM, tri4, CXCR4 frameshift and SPI1 mutations were significantly associated with lower OS (P<0.05). These results argue for integration of both cytogenetic and molecular screening in evaluation of first-line WM patients.

P2, N=20, Not yet recruiting, M.D. Anderson Cancer Center

Moreover, various potential genetic biomarkers of venetoclax resistance have been proposed, including chromosome 17p deletion, trisomy 12, and TP53 loss or mutation. This manuscript provides an overview of biomarkers that could predict treatment response to venetoclax.

P1, N=30, Recruiting, Noah Merin | Trial completion date: May 2023 --> May 2024 | Trial primary completion date: May 2021 --> May 2022

Chronic lymphocytic leukemia patients carrying a single TP53 hit (chromosome 17p deletion or single TP53 mutation) demonstrate excellent progression-free and overall survival on ibrutinib compared to cases harboring multiple TP53 hits. Testing TP53 deletion/mutation combining FISH and deep next-generation sequencing should be performed for a correct patient evaluation.

P1, N=15, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2021 --> May 2022 | Trial primary completion date: May 2021 --> May 2022

P=N/A, N=59, Recruiting, AbbVie | N=250 --> 59

We also report unique miRNAs associated with patients with high tumor burden MM (clonal-PC>95%). Thus, in addition to prognostication and risk stratification, our data demonstrated the value of serum microRNAs in predicting initial response to Bortezomib-based treatment in NDMM.

P1b, N=48, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

Genomic sequencing of refractory/relapsed sarcomas showed a low mutation burden. RNA analysis resulted in identification of potential novel therapeutic targets. Further analysis of patient molecular subgroups and therapeutic strategies is ongoing.

P=N/A, N=250, Recruiting, AbbVie | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Dec 2022 --> Dec 2024

P1, N=27, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2019 --> Dec 2021

Analysis of expression profiles and the ultrastructure of zebrafish NB tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell-cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in NB metastasis in the context of MYCN overexpression.

In February 2019, paronychia (grade 1) developed in the patient's right foot's first toe; hence, topical gentamicin and taping therapy were performed. In July 2019, paronychia/granulation (grade 2) was aggravated and successfully treated with silver nitrate chemical cauterization and taping therapy. The patient was continuously treated with 420 mg/day IBR without dose reduction or discontinuation, resulting in successful disease control of CLL with del 17p.

The de novo PEL group had >1 TP53 mutation, hotspot TP53 mutations, and less common TP53 LOH compared to t-PEL. TP53 hotspot mutation in t-PEL were only observed in the presence of a strong predisposing condition. Overall, these findings show distinct TP53 genetic alterations in de novo PEL and t-PEL, possibly reflecting different selective fitness advantages associated with TP53 dysregulation.

P1b, N=58, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Dec 2021

P1, N=11, Completed, OHSU Knight Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Jul 2021 --> Sep 2020

P1, N=30, Not yet recruiting, Fred Hutchinson Cancer Research Center

P=N/A, N=250, Recruiting, AbbVie | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

P1, N=15, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2020 --> May 2021 | Trial primary completion date: May 2020 --> May 2021