The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton's tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 ...monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complete response, and incidence of most frequent grade 3-4 adverse event. We identified nine clinical trials encompassing 11 different treatments, with a total of 5288 CLL patients evaluated. We systematically performed separated network meta-analyses (NMA) to evaluate the efficacy/safety of each regimen in the conditions previously described to obtain the surface under the cumulative ranking curve (SUCRA) score, which was subsequently used to build separated ranking charts. Interestingly, the combination of obinutuzumab with acalabrutinib reached the top of the chart in each sub-analysis performed, with the exception of the del17/P53mut setting, where it was almost on par with the aCD20 mAbs/ibrutinib combination (SUCRA aCD20-ibrutinib and O-acala: 93.5% and 91%, respectively) and of the safety evaluation, where monotherapies (acalabrutinib in particular) gave better results. Finally, considering that NMA and SUCRA work for single endpoints only, we performed a principal component analysis to recapitulate in a cartesian plane the SUCRA profiles of each schedule according to the results obtained in each sub-analysis, confirming again the superiority of aCD20/BTKi or BCL2i combinations in a first-line setting. Overall, here we demonstrated that: (1) a chemotherapy-free regimen, such as the combination of aCD20 with a BTKi or BCL2i, should be the preferred treatment choice despite biological/molecular characteristics (preferred regimen O-acala); (2) there is less and less room for chemotherapy in the first line treatment of CLL.
Mitochondrial alterations, often dependent on unbalanced mitochondrial dynamics, feature in the pathobiology of human cancers, including multiple myeloma (MM). Flavanones are natural flavonoids ...endowed with mitochondrial targeting activities. Herein, we investigated the capability of Hesperetin (Hes) and Naringenin (Nar), two aglycones of Hesperidin and Naringin flavanone glycosides, to selectively target Drp1, a pivotal regulator of mitochondrial dynamics, prompting anti-MM activity.
Molecular docking analyses were performed on the crystallographic structure of Dynamin-1-like protein (Drp1), using Hes and Nar molecular structures. Cell viability and apoptosis were assessed in MM cell lines, or in co-culture systems with primary bone marrow stromal cells, using Cell Titer Glo and Annexin V-7AAD staining, respectively; clonogenicity was determined using methylcellulose colony assays. Transcriptomic analyses were carried out using the Ion AmpliSeq™ platform; mRNA and protein expression levels were determined by quantitative RT-PCR and western blotting, respectively. Mitochondrial architecture was assessed by transmission electron microscopy. Real time measurement of oxygen consumption was performed by high resolution respirometry in living cells. In vivo anti-tumor activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells.
Hes and Nar were found to accommodate within the GTPase binding site of Drp1, and to inhibit Drp1 expression and activity, leading to hyperfused mitochondria with reduced OXPHOS. In vitro, Hes and Nar reduced MM clonogenicity and viability, even in the presence of patient-derived bone marrow stromal cells, triggering ER stress and apoptosis. Interestingly, Hes and Nar rewired MM cell metabolism through the down-regulation of master transcriptional activators (SREBF-1, c-MYC) of lipogenesis genes. An extract of Tacle, a Citrus variety rich in Hesperidin and Naringin, was capable to recapitulate the phenotypic and molecular perturbations of each flavanone, triggering anti-MM activity in vivo.
Hes and Nar inhibit proliferation, rewire the metabolism and induce apoptosis of MM cells via antagonism of the mitochondrial fission driver Drp1. These results provide a framework for the development of natural anti-MM therapeutics targeting aberrant mitochondrial dependencies.
Background
Copy-number alterations of chromosome 1q are frequently found in multiple myeloma (MM) and are associated with poor prognosis. Recently, it has been demonstrated that the number of 1q ...copies correlates with a high-risk behavior (BA Walker et al, Leukemia 2019, TM Schmidt et al, Blood Cancer J 2019), but no data are available in carfilzomib-treated patients (pts). Here we aim at dissecting the role of Gain1q (3 copies of 1q) vs amplification 1q (Amp1q, ≥4 copies of 1q) in carfilzomib-treated NDMM pts enrolled in the randomized FORTE trial (NCT02203643).
Methods
Fluorescence in situ hybridization (FISH) in CD138+ purified bone marrow plasma cells (BMPCs) was centralized and performed at baseline. Two hundred BMPC nuclei from each sample were scored. The cut-off level for Gain1q was 10% of nuclei with ≥3 copies of 1q (mean plus 3 standard deviations of 1q alterations in BMPC from 15 healthy donors). The cut-off for Amp1q was 20% of nuclei with ≥4 copies of 1q.
In the FORTE trial, transplant-eligible NDMM pts were randomized to receive carfilzomib (K) lenalidomide (R) dexamethasone (d) induction followed by autologous stem-cell transplantation (ASCT) and KRd consolidation (KRd_ASCT), 12 KRd cycles (KRd12) or K-cyclophosphamide(C)-d induction, followed by ASCT and KCd consolidation (KCd_ASCT). After consolidation, pts were further randomized to receive KR vs R maintenance.
Results
A total of 474 pts were enrolled. Median follow-up from 1st randomization was 45 months (m). Evaluation of 1q by FISH was missing in 70 pts (15%), while in 4 pts (1%) FISH was present but the number of 1q copies was not evaluable. Among evaluable pts, chromosome 1q was normal in 219 (55%) pts, Gain1q was found in 129 (32%) pts, while Amp1q in 52 (13%). Gain1q- and Amp1q-positive pts were well distributed among treatment arms.
Baseline characteristics associated with Amp1q, compared to Gain1q, were LDH >upper limit of normal (P=0.002) and low hemoglobin (P=0.029) and platelets (P=0.044).
Best response to therapy was not significantly different in Normal 1q vs Gain1q vs Amp1q groups (≥very good partial response rates: 85% vs 84% vs 77%; stringent complete response rates: 52% vs 50% vs 38%). Best overall minimal residual disease negativity by flow cytometry (sensitivity 10-5) pre-maintenance was also not significantly different (55% vs 55% vs 44%, respectively).
In a multivariate analysis adjusted for treatment and Revised International Staging System (R-ISS), the risk of progression/death was significantly higher in the presence of Gain1q vs Normal 1q (HR 1.65, 95% CI 1.14-2.37, P=0.007) and the highest in the presence of Amp1q as compared to both Normal 1q (HR 3.04, 95% CI 1.99-4.65, P<0.001) and Gain1q (HR 1.84, 95% CI 1.21-2.81, P=0.004; Fig. 1A).
Median progression-free-survival (PFS) was not reached in the Normal 1q group, while Gain1q (53 m) and especially Amp1q (21.8 m) groups performed very poorly.
The presence of Amp1q vs Normal 1q (HR 5.88, 95% CI 3.10-11.17, P<0.001) and Gain1q (HR 3.13, 95% CI 1.73-5.68, P<0.001) predicted a lower overall survival as well (Fig. 1B).
Subgroup analysis on the presence/absence of concomitant high-risk features was performed. Gain1q predicted a lower PFS compared to Normal 1q in the presence of concomitant standard-risk features (ISS 1, ISS 2, standard-risk cytogenetics) but not in the presence of high-risk disease (ISS 3, high-risk cytogenetics). On the other hand, the worse prognosis of Amp1q pts was confirmed across all subgroups.
A subgroup analysis according to the upfront treatment received was performed. Interestingly, treatment with KRd_ASCT completely abrogated the risk conferred by Gain1q (HR 1.25 vs Normal 1q, 95% CI 0.58-2.7, P=0.565), while Amp1q-positive pts still showed a very poor outcome (median PFS 17 m, HR 6.03 vs Normal 1q, 95% CI 2.78-13.1, P<0.001).
In KCd_ASCT and KRd12-treated pts, the 3 groups performed similarly to the overall population.
Conclusion
This is a first report on the prognostic role of the number of 1q copies in carfilzomib-treated NDMM pts. Having ≥4 copies of 1q universally predicts a very poor PFS and OS despite the use of a 2nd generation proteasome inhibitor upfront. On the other hand, KRd_ASCT completely abrogated the PFS disadvantage conferred by 3 copies of 1q.
RNA sequencing on representative samples of Normal 1q vs Gain1q vs Amp1q is in progress to explore differentially expressed genes in Amp1q pts that could be exploited in future treatment strategies.
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D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Giuliani:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Participation in congresses, Research Funding; Janssen Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Other: Clinical study sponsorship; participation in congresses, Research Funding; Millennium Pharmaceutical: Other: Clinical study sponsorship, Research Funding; GSK: Other: Clinical study sponsorship, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: Participation in congresses. Tacchetti:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Bristol-Myers Squibb: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Boccadoro:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Gay:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.
The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).
Analyzing gene expression profiles (GEP) through artificial intelligence provides meaningful insight into cancer disease. This study introduces DeepSHAP Autoencoder Filter for Genes Selection ...(DSAF-GS), a novel deep learning and explainable artificial intelligence-based approach for feature selection in genomics-scale data. DSAF-GS exploits the autoencoder’s reconstruction capabilities without changing the original feature space, enhancing the interpretation of the results. Explainable artificial intelligence is then used to select the informative genes for chronic lymphocytic leukemia prognosis of 217 cases from a GEP database comprising roughly 20,000 genes. The model for prognosis prediction achieved an accuracy of 86.4%, a sensitivity of 85.0%, and a specificity of 87.5%. According to the proposed approach, predictions were strongly influenced by CEACAM19 and PIGP, moderately influenced by MKL1 and GNE, and poorly influenced by other genes. The 10 most influential genes were selected for further analysis. Among them, FADD, FIBP, FIBP, GNE, IGF1R, MKL1, PIGP, and SLC39A6 were identified in the Reactome pathway database as involved in signal transduction, transcription, protein metabolism, immune system, cell cycle, and apoptosis. Moreover, according to the network model of the 3D protein-protein interaction (PPI) explored using the NetworkAnalyst tool, FADD, FIBP, IGF1R, QTRT1, GNE, SLC39A6, and MKL1 appear coupled into a complex network. Finally, all 10 selected genes showed a predictive power on time to first treatment (TTFT) in univariate analyses on a basic prognostic model including IGHV mutational status, del(11q) and del(17p), NOTCH1 mutations, β2-microglobulin, Rai stage, and B-lymphocytosis known to predict TTFT in CLL. However, only IGF1R hazard ratio (HR) 1.41, 95% CI 1.08-1.84, P=0.013), COL28A1 (HR 0.32, 95% CI 0.10-0.97, P=0.045), and QTRT1 (HR 7.73, 95% CI 2.48-24.04, P<0.001) genes were significantly associated with TTFT in multivariable analyses when combined with the prognostic factors of the basic model, ultimately increasing the Harrell’s c-index and the explained variation to 78.6% (versus 76.5% of the basic prognostic model) and 52.6% (versus 42.2% of the basic prognostic model), respectively. Also, the goodness of model fit was enhanced (χ2 = 20.1, P=0.002), indicating its improved performance above the basic prognostic model. In conclusion, DSAF-GS identified a group of significant genes for CLL prognosis, suggesting future directions for bio-molecular research.
Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, ...multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (
< 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections-PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments-identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.
The anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who received at least three prior lines of ...therapy, including proteasome inhibitor and immunomodulatory agent. A retrospective multicentric study was designed to evaluate feasibility, tolerability, and efficacy of daratumumab in monotherapy in RRMM.
This study included 44 consecutive RRMM patients that underwent daratumumab monotherapy after a median number of four prior therapies (range 2-9). Patients were treated in seven Sicilian centers, as part of Sicilian Myeloma Network and three Calabrian centers outside of controlled clinical trials from August 2016 through July 2020.
The regimen was well tolerated with few grade 3-4 haematological and rare non-haematological adverse events, such as pneumonia. Definitive discontinuation was due to disease progression in 25 (57%) patients. Since three patients did not complete at least one full cycle, a total of 41 patients was evaluated for response. Overall response rate was 37%, and the disease control rate (stable disease or better) was high (73%). The best achieved responses within 6 months were very good partial remission or better (27%), partial remission (10%), minimal response (14%) and stable disease (22%). After a median follow up of 7.8 months, median progression free survival (PFS) was 7.2 months and overall survival (OS) 7.8 months. Univariate analysis showed that patients with PR or better after 6 months of therapy had longer median PFS and OS (respectively 29.5 vs 3.6 months, p=0.0001 and 30.6 vs 3.9 months p=0.0001), confirmed by multivariate analysis. Furthermore, standard cytogenetic risk and biochemical relapse type had prolonged median PFS, but not OS (respectively unreached vs 2.6, p=0.03 and 23.9 vs 6.2, p=0.05) in both univariate and multivariate analysis. Additionally, univariate analysis showed that patients treated with carfilzomib-lenalidomide-dexamethasone prior to daratumumab had significantly shorter PFS compared to pomalidomide-dexamethasone (3.4 months vs 9.3 months, p=0.03), that multivariate analysis failed to confirm.
Our findings indicate that daratumumab as single agent is safe and well-tolerated regimen in real-life, associated to prolonged PFS and OS in responding patients. No new safety signals were identified.
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