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A series of 19 novel pyrido-imidazodiazepinones, with modulations of positions 2, 3 and 4 of the diazepine ring were synthesised and screened for their in vitro cytotoxic activities against two melanoma cell lines (A375 and MDA-MB-435) and for their potential toxicity against NIH-3T3 non-cancerous cells. Selected compounds were also evaluated on the NCI-60 cell line panel. The SAR study revealed that the molecular volume and the cLogP of compounds modified at position 2 were significantly correlated with the activity of these compounds on melanoma cell lines. Moreover, introduction of a heterocyclic group at position 2 or an azido-alkyl chain at position 4 led to compounds displaying a significantly different activity profile on the NCI-60 cell line panel, compared to phenyl-substituted compounds at position 2 of the diazepinone. This study provides us crucial information for the development of new derivatives active against melanoma.

Multiple myeloma (MM) is a hematologic cancer characterized by accumulation of malignant plasma cells in the bone marrow. To date, no definitive cure exists for MM and resistance to current treatments is one of the major challenges of this disease. The DNA helicase BLM, whose depletion or mutation causes the cancer-prone Bloom’s syndrome (BS), is a central factor of DNA damage repair by homologous recombination (HR) and genomic stability maintenance. Using independent cohorts of MM patients, we identified that high expression of BLM is associated with a poor outcome with a significant enrichment in replication stress signature. We provide evidence that chemical inhibition of BLM by the small molecule ML216 in HMCLs (human myeloma cell lines) leads to cell cycle arrest and increases apoptosis, likely by accumulation of DNA damage. BLM inhibition synergizes with the alkylating agent melphalan to efficiently inhibit growth and promote cell death in HMCLs. Moreover, ML216 treatment re-sensitizes melphalan-resistant cell lines to this conventional therapeutic agent. Altogether, these data suggest that inhibition of BLM in combination with DNA damaging agents could be of therapeutic interest in the treatment of MM, especially in those patients with high BLM expression and/or resistance to melphalan.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by marrow fibrosis, splenomegaly, constitutional symptoms and cytopenia with a proinflammatory and profibrotic cytokine phenotype involving the JAK-STAT pathway. Ruxolitinib is a JAK 1/2 inhibitor with proven efficacy on splenomegaly and constitutional symptoms, but it does not reverse fibrosis or the risk of leukemic transformation. While hematopoietic stem cell transplantation remains the only curative approach, it is still associated with a relatively high non-relapse mortality (NRM) rate, partly due to GVHD. The potential role of ruxolitinib or its withdrawal on NRM remains to be elucidated, and inflammatory cytokines might be implicated. In this report, we compared cytokine profiles in patients with myelofibrosis not treated with ruxolitinib ( n  = 18) or who received ruxolitinib and stopped it at conditioning regimen initiation ( n  = 53), at three different time points. At baseline, MF patients without ruxolitinib had increased inflammatory cytokine levels (CD25, REG3A, IL18 and ST2) as compared to MF patients on ruxolitinib. On day 0 and week 1 post-transplantation, levels of these cytokines were similar with and without ruxolitinib. On the other hand, cytokine levels at baseline did not predict grades 2–4 acute GVHD or hyperacute GVHD. These findings suggest that baseline cytokine profile in MF patients does not impact the risk of GVHD. Stopping ruxolitinib just before conditioning regimen may not influence GVHD risk more than in MF patients who have not received ruxolitinib. The potential benefit of a later ruxolitinib discontinuation on D0 or after transplantation ruxolitinib requires further investigation.

Background Some injectable medicines introduced recently allow patients with multiple myeloma (MM) to receive their chemotherapy at home. This study aimed at describing adult patients with MM receiving injectable chemotherapy via hospital‐at‐home (HAH) services and outpatient hospital units (OHUs) in metropolitan France in 2019 and 2020, analyzing the factors influencing HAH use, and evaluating the geographic variations and the evolution over time of HAH use by these patients during the study period. Methods Real‐world data from the French Hospital Discharge Database (PMSI) were analyzed. Results In total, 2169/9278 patients (23.4%) received at least one HAH chemotherapy injection. These patients were diagnosed more recently (mean ± standard deviation = 25.1 ± 19.6 vs. 31.6 ± 21.8 months), and lived in larger and wealthier cities (59,000 vs. 41,000 inhabitants; €23,300 ± €5300 vs. €21,700 ± €4100) and closer to their follow‐up hospital (18.7 ± 18.4 vs. 31.3 ± 31.2 km) than patients exclusively treated in OHUs (p < 0.001). Receiving bortezomib and carfilzomib, and the first chemotherapy dose in 2020, were the most significant factors associated with HAH use (odds ratio [95% confidence interval]: 6.12 [5.40–6.96], 2.01 [1.69‐2.39], and 1.81 [1.57–2.09], respectively, p < 0.001). HAH use increased between 2019 and 2020 (patients, +23%; administrative departments, +25%), likely related to the COVID‐19 pandemic. However, HAH use remained limited overall and exhibited inter‐regional variability. Infection‐related hospitalizations remained stable. Conclusions Receiving chemotherapy injections at home is feasible and safe, but further development and equitable access are essential to enhance patients’ quality of life and reduce costs.

BackgroundMultiple myeloma (MM) is the second most common hematologic malignancy. Aberrant epigenetic modifications have been reported in MM and could be promising therapeutic targets. As response rates are overall limited but deep responses occur, it is important to identify those patients who could indeed benefit from epigenetic-targeted therapy.MethodsSince HDACi and DNMTi combination have potential therapeutic value in MM, we aimed to build a GEP-based score that could be useful to design future epigenetic-targeted combination trials. In addition, we investigated the changes in GEP upon HDACi/DNMTi treatment.ResultsWe report a new gene expression-based score to predict MM cell sensitivity to the combination of DNMTi/HDACi. A high Combo score in MM patients identified a group with a worse overall survival but a higher sensitivity of their MM cells to DNMTi/HDACi therapy compared to a low Combo score. In addition, treatment with DNMTi/HDACi downregulated IRF4 and MYC expression and appeared to induce a mature BMPC plasma cell gene expression profile in myeloma cell lines.ConclusionIn conclusion, we developed a score for the prediction of primary MM cell sensitivity to DNMTi/HDACi and found that this combination could be beneficial in high-risk patients by targeting proliferation and inducing maturation.

Dear Editor, Even at the era of T-cell redirecting therapies, patients with relapsed or refractory multiple myeloma (RRMM) presenting extramedullary disease (EMD) and/or high risk cytogenetic abnormalities (HRCA) constitute a particularly challenging subgroup with lower overall response rate (ORR) and poorer survival outcomes [1, 2]. Patient/treatment characteristics and safety outcomes. n(%) N = 44 patients Median age, years-old 66 (min-max: 45–82) Female, n(%) 22 (50) Median of prior lines 4 (min-max : 2–9) Triple class refractory, n(%) 41 (93) ISS score III, n(%) 20 (48) Cytogenetic abnormalities, n(%) 22 (50)  17p deletion 9 (20)  1q21 gain 5 (11)  t(4; 14) 3 (7)  t(14; 16) 2 (4)  Del1p32 2 (4)  1q21 amplification 1 (2) Extramedullary disease, n(%) 22 (50) Number of involved sites, n(%)  1 4 (9)  2 5 (11)  ≥3 10 (23) Type of localization, n(%)  Cerebral 2 (4)  Lung 4 (9)  Liver 3 (7)  Kidney 3 (7)  Digestive 7 (16)  Cutaneous 8 (18)  Muscle 5 (11)  ORL 1 (2) High plasma cell infiltration, n(%) 12 (28) Acute kidney failure, n(%) 14 (32) Hypercalcemia, n(%) 10 (23) Number of cycles of chemotherapy, n(%)  1 30 (68)  2 7 (16)  ≥3 7 (16) Alkylating agent, n(%) 39 (89)  Cyclosphosphamide 37 (84)  Bendamustine 5 (11)  Belustine 1 (2.3) Anthracycline agent, n(%) 15 (34) Etoposide 22 (50) Vincristine 4 (9.1) Cisplatin 7 (16) Other 9 (20) Anti-BCMA bispecific, n(%)  Teclistamab 31 (70)  Elranatamab 13 (30) Delay between chemotherapy and bispecific, median days (min-max) 28 (4–197) CRS rate, n(%) 28 (64)  Grade 1 21 (75)  Grade 2 6 (21)  Grade 3 1 (3.6) ICANS rate, n(%) 3 (7)  Grade 1 2 (67)  Grade 2-3 0  Grade 4 1 (33) Tocilizumab use, n(%) 10 (23) Dexamethasone use, n(%) 4 (9.1) Infection, n(%)  Grade 3 infection 12 (80)  Ig supplementation therapy 35 (80)  Antipneumocystisis agent 38 (89)  Antibioprophylaxis 24 (55)  Antiviral agent 43 (98)  Grade 3 cytopenias, n(%) 14 (33) Concerning chemotherapy regimen, the most frequent class used was alkylating agent in 89% (n = 39), followed by anthracycline in 34% (n = 15), etoposide in 50% (n = 22), cisplatin in 16% (n = 7) and vincristine in 9.1% (n = 4). Conversion of response rate was reported on Fig. 1B. Fig. 1 Response rate, response conversion over cycles, progression free survival and overall survival.

The present study aimed at describing the outcome of patients with HIV-associated lymphomas following autologous hematopoietic stem cell transplantation (autoHCT) in the rituximab and combined antiretroviral therapy (cART) era. Eligible for this retrospective study were HIV-positive patients with lymphoma who received autoHCT between 2007 and 2013. A total of 118 patients were included with a median age of 45 years (range 24–66). Underlying diagnoses were diffuse large B cell lymphoma in 47%, Hodgkin lymphoma in 24%, Burkitt lymphoma in 18%, and plasmablastic lymphoma in 7% of patients. Disease status at autoHCT was complete remission in 44%, partial remission (PR) in 38%, and less than PR in 18% of the patients. With a median follow-up of 4 years, 3-year non-relapse mortality, incidence of relapse, progression-free survival (PFS) and overall survival (OS) were 10%, 27%, 63% and 66%, respectively. By multivariate analysis, disease status less than PR but not CD4+ cell count at the time of autoHCT was a significant predictor of unfavorable PFS and OS. In conclusion, in the era of cART and chemoimmunotherapy, the outcome of autoHCT for HIV-related lymphoma is driven by lymphoma-dependent risk factors rather than by characteristics of the HIV infection.

Background Multiple myeloma (MM) is a malignant plasma cell disease with a poor survival, characterized by the accumulation of myeloma cells (MMCs) within the bone marrow. Epigenetic modifications in MM are associated not only with cancer development and progression, but also with drug resistance. Methods We identified a significant upregulation of the polycomb repressive complex 2 (PRC2) core genes in MM cells in association with proliferation. We used EPZ-6438, a specific small molecule inhibitor of EZH2 methyltransferase activity, to evaluate its effects on MM cells phenotype and gene expression prolile. Results PRC2 targeting results in growth inhibition due to cell cycle arrest and apoptosis together with polycomb, DNA methylation, TP53, and RB1 target genes induction. Resistance to EZH2 inhibitor is mediated by DNA methylation of PRC2 target genes. We also demonstrate a synergistic effect of EPZ-6438 and lenalidomide, a conventional drug used for MM treatment, activating B cell transcription factors and tumor suppressor gene expression in concert with MYC repression. We establish a gene expression-based EZ score allowing to identify poor prognosis patients that could benefit from EZH2 inhibitor treatment. Conclusions These data suggest that PRC2 targeting in association with IMiDs could have a therapeutic interest in MM patients characterized by high EZ score values, reactivating B cell transcription factors, and tumor suppressor genes.

Aims/Background Recent agents have profoundly reshaped the multiple myeloma (MM) landscape. Their real‐world impacts need to be assessed over the long term. Methods EMMY is a non‐interventional, prospective dynamic cohort, conducted in France, since 2017, with 900 patients enrolled each year. Newly diagnosed MM (NDMM) who initiated a treatment from 2017 to 2020 are here described. Results A total of 1036 non‐transplant eligible (NTE) patients (median age: 74.9 years) and 561 patients who received autologous stem cell transplantation (ASCT) (median age: 60.6 years) were enrolled. For ASCT patients, a shift in induction treatment from bortezomib‐thalidomide‐dexamethasone (VTd) (29.1%) to bortezomib‐lenalidomide‐dexamethasone (VRd) (55.1%) marked the period. Maintenance treatment with R after ASCT became a standard (75% of patients). In NTE patients, R‐based regimens were increasingly used from 29.4% in 2017 (of whom Rd.: 17.0%, VRd: 10.6%) to 73.3% in 2020 (of whom Rd.: 21.8%, VRd: 48.5%). Median progression‐free survival (mPFS) was 46.5 months (95% CI: 37.8–50.6) and 18.7 months (95% CI: 16.3–20.8) in ASCT and NTE patients, respectively. In the ASCT group, patients treated with and without R maintenance had a mPFS of 51.8 (95% CI: 44.1–NA) and 29.6 months (95% CI: 21.8–40.9), respectively. In the NTE group, the mPFS was 26.3 (95% CI: 21.9–30.9) and 14.6 months (95% CI: 11.9–17.7) in patients who received an R‐based and non‐R‐based regimen, respectively. The estimated 48‐month overall survival rates were 89% (95% CI: 84.5–92.2) and 63% (95% CI: 58.5–67.1) for ASCT and NTE patients, respectively. Conclusions The 2017–2020 period was marked by the expansion of R use in both NDMM ASCT and NTE patients. A total of 1036 non‐transplant eligible (NTE) patients and 561 patients who received autologous stem cell transplantation (ASCT) were enrolled in Emmy. In the ASCT group, patients treated with and without R maintenance had a mPFS of 51.8 (95% CI: 44.1–NA) and 29.6 months (95% CI: 21.8–40.9), respectively. In the NTE group, the mPFS was 26.3 (95% CI: 21.9–30.9) and 14.6 months (95% CI: 11.9–17.7) in patients who received an R‐based and non‐R‐based regimen, respectively. The 2017–2020 period was marked by the expansion of R use in both NMDD ASCT and NTE patients.