Chr del(17p)

Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, like bortezomib, with an autophagy inducer, like rapamycin, may improve patient outcomes in MM, where low GABARAP in the form of del(17p) is common and leads to worse outcomes.

P1, N=18, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024

The "immuno-flowFISH" imaging flow cytometric method could detect del(17p) in plasma cells in both bone marrow and blood samples of myeloma patients. This method was also able to detect gains and losses of chromosome 17, which are also of prognostic significance. The lowest levels of 0.009% (bone marrow) and 0.001% (blood) for chromosome 17 abnormalities was below the detection limit of current FISH method. This method offers potential as a new means of identifying these prognostically important chromosomal defects, even when only rare cells are present and for serial disease monitoring.

P1/2, N=20, Active, not recruiting, Ciusss de L'Est de l'Île de Montréal | Trial primary completion date: Sep 2021 --> Oct 2023

Our analysis revealed that specific genetic mutations and chromosomal alterations are strongly associated with the disease's course and patient prognosis. Particularly, the presence of unmutated IGHV and TP53 mutations emerged as key indicators of a more aggressive disease course and shorter treatment-free intervals. These findings underscore the critical role of advanced genetic testing in identifying patients who may require more intensive treatment and monitoring.

P1, N=58, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1 | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Chromosome 1 structural abnormalities were the most prevalent, found in 65% of cases. The frequent presence of subclones and composite karyotypes underscored the genomic heterogeneity and instability in this cohort.

P2, N=107, Recruiting, West China Hospital of Sichuan University; West China Hospital, Sichuan University

Post transplant treatment included lenalidomide maintenance, followed by a variety of salvage regimens over the next 7 years including thalidomide, carfilzomib, daratumumab and pomalidomide...He received a second ASCT after melphalan 140 mg/m2 in Oct 2017 followed by recovery of normal blood counts...Case 3 = 65-year-old man with MM treated with bortezomib + dexamethasone followed by ASCT in Aug 2012...Six months of decitabine did not improve his blood counts...This approach was well tolerated and provided durable hematopoietic recovery. Second ASCT using banked autologous stem cells should be considered in such patients who are not otherwise candidates for allogeneic transplantation.

P1, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2024 --> May 2025

P3, N=553, Active, not recruiting, AstraZeneca | Phase classification: P3b --> P3

Our study confirms that TP53 mutations result in shorter PFS and OS in CLL. We demonstrate improved PFS when patients with ATM or RPS15 mutations are treated with IR compared to FCR. Mutations in the CREBBP gene have recently been described as a novel candidate driver in CLL.

The phase 2 trial of Ven added to alternating Clad+LDAC and Aza showed promising remission rates of 57% in pts with ND AML having TP53 mut/loss and high rates of MRD negativity in responders; median RFS and OS was not reached at 9 mos follow-up. Five pts (36% overall, and 50% of the responders) could be consolidated with HSCT, with none of them relapsing after HSCT. The trial continues to accrue pts.

TP53 mutation status was not different between MDS and AML, but 17p deletion was observed at approximately 40% in MDS-H and AML, much higher than in MDS-L. Multi-hit TP53 mutation based on WHO 2022 and ICC was present at a relatively high frequency at 60-80% in MDS and AML with TP53 mutations. In particular, when ICC criteria were applied to MDS, 20% more patients were reclassified into TP53 mutation-related MDS or MDS/AML subgroup than when WHO 2022 criteria were applied.

In the GOELAMS model, 42% of intermediate risk patients were considered high (10%) or very high risk (32%) in the new model. Conclusion Analysis of clinical, cytogenetic and molecular variables identified nine variables for a new prognostic model which was associated with distinct OS at 1 year after first AML relapse and improved prognostic accuracy.

Disease relapse typically occurs regardless of treatment with proteasome inhibitors (such as bortezomib and carfilzomib), immunomodulatory drugs (such as lenalidomide and pomalidomide), anti-CD38 monoclonal antibodies (such as daratumumab and isatuximab) or myeloablative melphalan and autologous stem cell transplantation, and also occurs following treatment with immunotherapeutics such as bispecific antibodies and/or CAR-T cells (targeting BCMA, FcRH5 or GPRC5D). We propose that cure of MM requires eradication of MM progenitor cells alongside plasma cells. We are currently conducting scRNA-seq and CITE-seq studies of primary MM samples to further characterize MM progenitor cells for gene and protein expression in order to define their optimal therapeutic targets.

Through single-cell transcriptomics, we were able to capture, in high granularity, the TIME and correlate specific immune cell populations and phenotypes with relapse risk and poor prognostic outcomes. These results suggest that immune subpopulations may be an essential novel aspect for improving current risk stratification models.

AntiCD38 monoclonal antibody (mAb) was part of induction in 125 (84%) pts [68 pts quadruplet containing carfilzomib; 53 pts quadruplet containing bortezomib], 28 pts received triplets. The use of antiCD38 mAb in induction regimens or dose of melphalan does not impact the effect of ASCT on MM clone size, likely owing to the distinct mechanism of action of melphalan. This dataset provides context to explore risk- and response-adapted use of ASCT and use of new cellular and non-cellular immunotherapies as post-induction consolidative strategies.

Like with other BTK inhibitors, ibrutinib and acalabrutinib, IGHV mutational status did not affect PFS outcome (Bartosz et al. 2015). This study provides further evidence that zanu is a valuable first-line treatment option for pts with CLL/SLL.

These results indicate distinct bone marrow microenvironments of HR and SR MM. CD4 and CD8 T cells appear to be more activated in HR patients compared to SR. However, the higher frequencies of mast cells and plasmacytoid dendritic cells, and the prominent expression of ISGs associated with inhibition of anti-tumor immunity suggest dysregulation and exhaustion of T cell activity in HR patients.

This Q-TWiST analysis demonstrated a statistically significant gain in quality-adjusted survival with zanubrutinib compared with ibrutinib in patients with high-risk R/R CLL. The slightly longer TOX duration in patients receiving zanubrutinib versus those receiving ibrutinib could be explained in part by better treatment adherence. The results of this Q-TWiST analysis, which integrates both the length and quality of survival in addition to efficacy and toxicity, provide valuable insights that may help to inform clinical decision-making in the treatment of patients with R/R CLL.

P2, N=40, Completed, Maisonneuve-Rosemont Hospital | Active, not recruiting --> Completed

Venetoclax was initiated and a second allo-HSCT was planned. This is, to the best of our knowledge, the first reported case of DCL as cause of prolonged cytopenia in a patient after CAR-T-Cell therapy. Cytopenia after CAR-T-Cell therapy is common and mostly attributed to lymphodepletion, bridging-therapy or severe CRS. Prolonged/recurrent cytopenia is reported in a various rate (up to 40% at d+90 in Ide-Cel RWD) and different mechanisms have been discussed.

Composite karyotype, rare t(3;3) double minutes, +11,+13, del(9q), and del(Xq) were the novel findings reported in the South Canara region of Karnataka. Despite other molecular techniques, conventional cytogenetics remains the baseline in the diagnosis of malignancies.

Ibrutinib or zanubrutinib combined with bendamustine (B) and rituximab therapy has been confirmed to be associated with promising activity for CLL/SLL through fixed-duration therapy [4]. This phase II study is expected to provide a treatment option for patients with CLL/SLL who are ineligible for intensive chemotherapy.

(1) OGM is a robust method to assess genome wide aberrations in CLL genome-wide; (2) Its independence of cell cultures and a higher genomic resolution increases the detection rate of genomic complexity. To define clear genomic complexity criteria by OGM, additional studies are needed and its clinical impact should be validated; (3) OGM sensitivity is limited and small cell clones (<15–25%) could be missed. Thus, FISH for del17p (TP53) detection should be maintained in the routine management of CLL patients.

Approximately one-third of newly diagnosed CLL patients do not have FISH analysis performed and when done, half of all the FISH analysis are done within the first three months of diagnosis. The presence of del17p confers an inferior survival compared to non-del17p. Pts with del17p have a shorter TTTI however time to treatment initiation does not influence rwOS.

main study Substudy patients treated with VenR (n = 194) patients treated with BR (n = 195) patients retreated with VenR (n = 25) Baseline characteristics mean age, years (SD) 63.9 (10.5) 64.4 (9.6) 65.8 (8.3) Number of prior cancer therapy, n (%) 1 111 (57.2) 117 (60.0) 0 (0.0) 2 58 (29.9) 43 (22.1) 20 (80.0) ≥3 25 (12.9) 35 (17.9) 5 (20.0) del(17p) and/or TP53 mutation (aCGh), n (%) mutated 53 (27.3) 55 (28.2) 14 (56.0) unmutated 104 (53.6) 98 (50.3) 9 (36.0) unknown 37 (19.1) 42 (21.5) 2 (8.0) Genomic complexity, n (%) n = 48 n = 46 n = 20 3–4 34 (70.8) 29 (63.0) 3 (15.0) ≥5 14 (29.2) 17 (37.0) 8 (40.0) iGhV, n (%) n = 180 n = 180 n = 23 mutated 53 (29.4) 51 (28.3) 2 (8.7) unmutated 123 (68.3) 123 (68.3) 21 (91.3) unknown 4 (2.2) 6 (3.3) 0 (0.0) efficacy results median follow-up, months 85.7 85.7 33.4 Best oRR, % 93.3 67.7 72.0 umRD at eoCT of main study, n (%) 121 (62.4) 26 (13.3) 16 (64.0) umRD at eoCT of substudy, n (%) N/a N/a 8 (32.0) umRD at eoT of main study, n (%) 83 (70.3)* N/a 14 (56.0) umRD at eoT of substudy, n (%) N/a N/a 0 (0.0) median pFS, months (95% Ci) 54.7 17.0 23.3 (52.3, 59.9) (15.5, 21.7) (15.6, 24.3) 3-year oS rate, % (95% Ci) 88.4 78.9 53.1 (83.8, 93.0) (72.8, 84.9) (25.1, 81.0) *patients who completed 2 years of Ven without pD (n = 118) aCGh: array comparative genomic hybridization; BR: bendamustine- rituximab; Ci: confidence interval; del(17p): deletion in chromosome 17p; eoCT: end of combination treatment; eoT: end of treatment; iGhV immu- noglobulin heavy chain gene; oRR: overall response rate; oS: overall sur- vival; pD: progressive disease; pFS: progression free survival; SD: standard deviation; TP53: tumor protein p53; umRD: undetectable minimal residual disease; Ven(R): venetoclax-(rituximab) cBTKi pre-treated CLL pts treated with pirtobrutinib monotherapy in the phase 1/2 BRUIN trial (NCT03740529) who subsequently developed disease progression (PD) were included in this analysis...Pts received one or more of the following cBTKi: ibrutinib (n = 44, 90%), acalabrutinib (n = 10, 20%), or zanubrutinib (n = 1, 2%)... Pts who progressed on pirtobrutinib showed clearance of BTK C481 clones and the emergence or outgrowth of non-C481 clones, particularly gatekeeper T474 and kinase-impaired L528W mutations, as well as other VUS. Many acquired BTK mutations were shown to pre-exist at baseline at low VAF, reflecting emergence on prior cBTKi. Importantly, these baseline kinase domain BTK mutations did not preclude pirtobrutinib efficacy.

Patients who did not have del(17p) during follow-up showed the best outcomes, whereas those who acquired del(17p) during their disease course, experienced compromised survival (mOS: 61.3 months vs. 49.4 months, HR = 1.64, 95% CI: 1.06-2.56, P < 0.05). In conclusion, our data confirmed the adverse impact of a minor clone of del(17p) at relapse and highlighted the importance of designing optimal therapeutic strategies to eliminate high-risk CAs.

P1, N=30, Active, not recruiting, Noah Merin | Trial completion date: May 2024 --> Nov 2031

Patients receiving first-line therapy were divided into three cohorts: venetoclax (VEN) + hypomethylating agents (HMAs; Cohort A), intensive chemotherapy (Cohort B), or HMA without VEN (Cohort C)...Median overall survival (95% CI) was 7.4 months (6.0-8.8) for Cohort A, 9.4 months (7.2-10.4) for Cohort B, and 5.9 months (4.3-7.5) for Cohort C. There were no differences in survival by treatment type after adjusting for the effects of relevant covariates (Cohort A vs. C adjusted hazard ratio &lsqb;aHR] = 0.9; 95% CI, 0.7-1.3; Cohort A vs. B aHR = 1.0; 95% CI, 0.7-1.5; and Cohort C vs. B aHR = 1.1; 95% CI, 0.8-1.6). Patients with TP53m AML have dismal outcomes with current therapies, demonstrating the high unmet need for improved treatments.

No superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post-transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.

If prior CIT, I no longer recommend re-treatment with CIT, regardless of duration of previous response, given the consistent evidence for superiority of targeted agents over CIT (discussed below), unless low intensity therapy such as oral chlorambucil or cyclophosphamide is used for purely palliative symptom control...The resulting score was clustered as low (0–1), intermediate (2–3) or high (4) and stratified probability of 24-month overall survival as 88%, 64%, and 44%, respectively in an external validation cohort.41 Among the choices of targeted agent drug classes, my least preferred are the PI3K inhibitors such as Idelalisib (±rituximab) as the efficacy is inferior and the toxicity profile,35, 42 especially infection risk and solid organ autoimmune complications (colitis/hepatitis/pneumonitis) are less favorable than the alternatives, as directly established in comparison against acalabrutinib in the ASCEND study.36 The major data from the most impactful randomized studies in R/R CLL are summarized in Table 2...The ELEVATE R/R study38 with acalabrutinib showed non-inferior PFS to ibrutinib (consistent in all biological subsets) but a clearly superior toxicity profile with lower rates of atrial arrhythmias, hypertension and cumulatively a lower cumulative toxicity burden.48 The ALPINE study compared zanubrutinib to ibrutinib and also displayed superior tolerability, fewer discontinuations and a lower rate of arrhythmias, but no difference in rates of hypertension (all grade; 21.9 vs. 19.8% and grade 3; 14.8 vs. 11.1%).39 A potential major advantage for zanubrutinib is that it also achieved statistically significantly superior PFS over ibrutinib (24 month rates of 79.5% vs. 67.3%; HR 0.65, p = 0.0024), but the PFS difference may in part be attributable to a relative “under performance” of ibrutinib in ALPINE relative to RESONATE and ELEVATE R/R.49 I personally prefer acalabrutinib or zanubrutinib over ibrtuinib noting that both have the slight inconvenience of twice daily dosing...2 TIME-LIMITED VENETOCLAX The early clinical evaluation and first regulatory approvals of venetoclax used a continuous single-agent treatment schedule,52 the largest clinical experience in the del(17p) subset used that approach,53, 54 and the most robust evaluation of prognostic factors for outcomes with venetoclax therapy was performed in a cohort predominantly so treated,55 identifying the following factors predictive of less durable disease control: bulky adenopathy (≥5 cm), disease refractoriness to either fludarabine or prior B-cell receptor inhibitors, TP53 aberrancy, and NOTCH1 mutation.55 While less durable than in BTKi-naïve disease, if BTKi refractory or intolerant, venetoclax is the preferred treatment with 70% response rate and median PFS of ∼24 months23. Combination therapy with an anti-CD20 antibody achieves a higher rate of uMRD (above 60% in R/R cohorts),56 enabling time-limited therapy for deep responders without evidence of impairing PFS relative to continuous therapy,57 and maintaining the opportunity for re-treatment with prolongation of duration of venetoclax benefit.57, 58 That approach with a fixed 24-month treatment duration was used in the MURANO study and compared to Bendamustine-rituximab.24, 30, 59, 60 The logistic complexities and resource burdens of the venetoclax dose-ramp up and tumor-lysis syndrome mitigation and monitoring, inconvenience of the parenteral anti-CD20 antibody administration are draw-backs from this approach, perhaps counterbalanced by the excellent tolerance and low adverse event rate beyond the first 6 months combination treatment period, and the attraction of time-limited therapy...4 RICHTER SYNDROME The development of Richter transformation as a clonally related evolution of underlying CLL is a profoundly adverse event and is usually fatal (median survival ∼6 months),1 unless able to receive a cellular immunotherapy (allogeneic transplant or CAR-T).65 The minority of patients where the DLBCL is clonally unrelated to their CLL, definitively recognized by comparative mutational analyses, but correlated with low expression of PD-1 by immunohistochemistry,66 is important to recognize, as their prognosis is far more favorable and may approach that of de novo DLBCL. Standard anthracycline- or ara-C/platinum-based regimens commonly used for DLBCL achieve response rates of 40%–65% but median PFS is consistently substantially less than 12 months (reviewed in ref #1) and clinical trials are therefore strongly preferred but have not shown major promise to date except for the addition of Venetoclax to DA-EPOCH-R,67 noting profound myelosuppression commonly encountered, and perhaps best utilized where subsequent allogeneic transplant can restore hematopoiesis,64 or inexplicably pirtobrutinib,68 despite low activity of other BTKi.

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

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.

Four phase-2 trials of the German CLL Study Group evaluated time-limited combination regimens in treatment-naïve or relapsed/refractory CLL: BAG (venetoclax-obinutuzumab), BCG (idelalisib- obinutuzumab), BIG (ibrutinib-obinutuzumab) and BIO (ibrutinib-ofatumumab), with or without initial debulking with bendamustine. Genetic risk factors such as the IGHV mutation status remain significant prognostic factors for PFS in the context of time-limited treatment with targeted drugs. Acquisition of high-risk markers was rare and resistance mutations were only acquired in 2 of 44 cases. Chronic lymphocytic leukemia, ibrutinib, Prognostic factor, Venetoclax