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In phase 1 of CC-92480- MM- 001 (NCT03374085), the recommended phase 2 dose (RP2D) of mezigdomide plus dexamethasone (MEZI-d) was selected at 1 mg once daily for 21/28 days. Here we report preliminary results from the MEZI-d dose-expansion cohort in patients with heavily pretreated RRMM. Key eligibility criteria were: RRMM;>=3 prior lines of therapy;disease progression <=60 days of last myeloma therapy;refractoriness to lenalidomide/pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody. Oral mezigdomide 1 mg was given on days 1-21 of each 28-day cycle, plus weekly dexamethasone (40 mg;20 mg if >75 years of age). Primary objective was to evaluate efficacy (overall response rate [ORR]);secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. As of 16/Sep/2022, 101 patients had received MEZI-d at the RP2D. Median age was 67 (range 42-85) years, median time since initial diagnosis was 7.4 (1.1-37.0) years;39.6% of patients had plasmacytomas and 37/101 patients had high-risk cytogenetics (56/101 not evaluable). Median number of prior regimens was 6 (3-15);prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%). All patients were refractory to last myeloma regimen and triple-class refractory. Median follow-up was 7.5 (0.5-21.9) months, with a median of 4 (1-20) cycles;10.0% of patients continued treatment;progressive disease was the main reason for discontinuation (60.4%). ORR was 40.6% for all patients. Whilst data are not mature yet, median PFS was 4.4 (95% CI 3.0-5.5) months and median duration of response was 7.6 (95% CI 5.4-9.5) months. ORR was 30.0% in patients with plasmacytomas (N = 40) and 50.0% in patients with prior anti-BCMA therapy (N = 30). Ninety-one (91.1%) patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). Most frequent hematologic grade 3/4 TEAEs were neutropenia (75.2%), anaemia (35.6%), and thrombocytopenia (27.7%);34.7% of patients had grade 3/4 infections, including grade 3/4 pneumonia (15.8%) and COVID-19 (7.0%). Occurrence of other grade 3/4 non-hematologic TEAEs was generally low. Due to TEAEs, 76.2% and 29.7% of patients had mezigdomide dose interruptions and reductions, respectively;90.1% of patients discontinued mezigdomide. Mezigdomide induced substrate degradation and increases in activated and proliferating T cells in patients, including those directly refractory to pomalidomide-based therapies. MEZI-d had a manageable safety profile with encouraging efficacy in patients with triple-class refractory RRMM, including patients with prior BCMA-targeted therapies. These results strongly support the continued development of mezigdomide in MM, and especially in combination.
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Introduction: Croatian National Cancer Registry of Croatian Institute for Public Health reported that in year 2020 lung cancer was the second most common cancer site diagnosed in men with 16% and the third most common in women with 10% incidence among all cancer sites. Unfortunatelly lung cancer has the highest mortality in both men and women. Haematological malignancies had 7% share in all malignancies in both male and female cances cases. In 2020 190 newly diagnosed cases of lymphatic leukemia in men and 128 cases in women were reporeted, meaning 1.5 and 1.2% of all malignancies, respectively. Chronic lymphatic leukemia (CLL) is an advanced age disease and incidence increases with age. Impaired immunity, T and B cell dysfunction in CLL, chromosomal aberations, long-term immunosuppressive therapy and genetic factors can all cause secondary malignancies. Co- occurence of solid tumors and CLL is very rare. Although patiens with CLL have an increased risk of developing second primary malignancies including lung carcinoma, the data about their clinical outcomes are lacking. Parekh et al. retrospectively analyzed patients with simultaneous CLL and lung carcinoma over a 20-year period, and they found that ~2% of patients with CLL actually developed lung carcinoma. The authors claimed that up to 38% of patients will also develop a third neoplasm more likely of the skin (melanoma and basal cell carcinoma), larynx (laryngeal carcinoma) or colon. Currently there are no specific guidelines for concurrent CLL and non-small cell lung carcinoma (NSCLC) treatment. Usually, when the tumors are diagnosed simultaneously, treatment is based to target the most aggressive malignancy, as the clinical outcomes depend on the response of the tumor with the poorest prognosis. For this reason, a multidisciplinary approach is mandatory. Case report: A patient with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation was diagnosed in 2019 (at the age of 71) with B chronic lymphocytic leukemia with bulky tumor (inguinal lymph nodes 8x5 cm), stage B according to Binet, intermediate risk. He was treated with 6 cycles of chemoimmunotherapy (rituximab/cyclofosfamid/fludarabine). In 10/2019 remission was confirmed, but MSCT described tumor in the posterior segment of upper right lung lobe measuring 20x17 mm and bilateral metastases up to 11 mm. Bronchoscopy and biopsy were performed, and EGFR neg, ALK neg, ROS 1 neg, PD-L1>50% adenocarcinoma was confirmed. He was referred to Clinical Hospital Center Osijek where monotherapy with pembrolizumab in a standard dose of 200 mg intravenously was started in 01/2020. Partial remission was confirmed in October 2020. Immunotherapy was discontinued due to development of pneumonitis, dysphagia and severe weight loss (20kg), but without radiologically confirmed disease progression. At that time he was referred to our hospital for further treatment. Gastroscopy has shown erosive gastritis with active duodenal ulcus, Forrest III. Supportive therapy and proton pump inhibitor were introduced. After complete regression of pneumonitis, improvement of general condition and resolution of dysphagia, no signs of lung cancer progression were found and pembrolizumab was reintroduced in 12/2021. Hypothyroidism was diagnosed in 01/2021 and levothyroxine replacement ther apy was started. In 03/2021 he underwent surgical removal of basal cell carcinoma of skin on the right temporal region with lobe reconstruction. From 02/2021, when pembrolizumab was reintroduced, regression in tumor size was continously confirmed with complete recovery of general condition. He was hospitalized for COVID 19 infection in 09/2021, and due to complications pembrolizumab was discontinued till 11/2021. Lung cancer immunotherapy proceeded till 11/2022, when Multidisciplinary team decided to finish pembrolizumab because of CLL relapse. CLL was in remission till August 2022 when due to B symptoms, lymphcytosis, anemia and generalized lymphadenopathy, hematological workup including biopsy of cervical lymph node was performed and CLL/SLL relapse was confirmed. Initially chlorambucil was introduced, but disease was refractory. Based on cytogenetic test results (IGHV unmutated, negative TP53) and due to cardiovascular comorbidity (contraindication for BTK inhibitors) venetoclax and rituximab were started in 01/2023. After just 1 cycle of treatment normal blood count as well as regression of B symptoms and peripheral lymphadenopathy occured, indicating the probability of complete disease remission. In our patient with metastatic lung adenocarcinoma excellent disease control is achieved during 41 month of treatment in first line setting. Furthermore, relapsed/refractory CLL/SLL is currently in confirmed remission. Conclusion(s): Successful treatment of patients with multiple primary malignancies is based on multidisciplinarity, early recognition and management of side effects, treatment of comorbidities with the aim of prolonging life, controlling symptoms of disease and preserving quality of life.
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The most common non-Hodgkin's lymphoma (NHL) is diffuse large B-cell lymphoma (DLBCL), an aggressive lymphoma that can be cured with standard frontline chemo-immunotherapy in 60%-70% of patients but with historically poor outcomes for relapsed/refractory disease. Patients with relapsed DLBCL after autologous stem cell transplant (ASCT) or with chemotherapy-refractory disease have a particularly dismal prognosis, with a median overall survival (OS) of only 6 months. Chimeric antigen receptor (CAR) T-cell therapy has significantly improved outcomes for patients with relapsed/refractory large B-cell lymphoma, mantle cell lymphoma and follicular lymphoma, with multiple FDA approved CAR T products now commercially available in many developed world including European countries. Ongoing studies seek to move CAR T cells to earlier lines of therapy and to characterise the efficacy and safety of CAR T-cell approaches in additional lymphoma histologies including relapsed/refractory follicular lymphoma and chronic lymphocytic leukaemias. Other areas of active research address CAR T in combination with other lymphoma-directed therapies, and mechanisms of CAR T resistance. We conducted a retrospective observational study assessing the outcomes of patients referred to our tertiary centre, University College London hospital NHS foundation Trust (UCLH) from January 2018 to December 2022, over a 48-month period. We collected data including patients' demographics, types of lymphomas, prior lines of therapies including stem cell transplantation, bridging therapies as appropriate, complications and overall response rate. We also analysed the communication between teams during the challenging period of the COVID-19 pandemic.
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Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (>= 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-offlight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Result(s): We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICIinsensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusion(s): Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer.
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Background: B-cell lymphoma-2 (Bcl-2) proteins play an important role in multiple myeloma (MM) cell survival and represent an attractive therapeutic target. In prior trials, a subgroup analysis of patients with t(11;14)-positive relapsed/refractory (R/R) MM showed the combination of a Bcl-2 inhibitor, a proteasome inhibitor, and dexamethasone improved progression-free survival with no increased mortality. BGB-11417, a Bcl-2 inhibitor, is more potent and selective than venetoclax. BGB-11417- 105 (NCT04973605) is a phase 1b/2 study assessing the safety and efficacy of BGB-11417 monotherapy, in combination with dexamethasone, or with dexamethasone+carfilzomib in patients with t(11;14)-positive R/R MM. Preliminary safety results for the combination of BGB-11417 + dexamethasone are presented. Method(s): Eligible patients had t(11;14)-positive R/R MM and had been exposed to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 therapy. Patients received 80-, 160-, 320-, or 640-mg BGB-11417 daily with 40-mg dexamethasone weekly until death, intolerability, or disease progression. Dose escalation was guided by a mTPI-2 design and overall review by a safety monitoring committee. Pharmacokinetics (PK) were also assessed. Result(s): As of 1 July 2022, 10 patients were enrolled in the 80-, 160-, and 320-mg (3 patients each) and 640-mg (1 patient) dose-escalation cohorts of BGB-11417 + dexamethasone. The median age was 69 years (range, 52-81) and median prior lines of therapy was 3 (range, 1-5). The median treatment duration was 3.2 months (range, 0.5-6.5). No patients experienced dose-limiting toxicity at any dose level. Three patients died whilst on study: 1 due to COVID-19 complications 157 days after treatment discontinuation (day 208), 1 due to progressive disease 50 days after treatment discontinuation (day 89), and 1 due to COVID-19 whilst on study treatment (day 78). No deaths were associated with study treatment. Two patients experienced Grade >= 3 treatment-emergent adverse events (TEAEs). One patient in the 160-mg cohort experienced Grade 3 increase in liver enzymes and lymphopenia. One patient in the 320-mg cohort experienced Grade 3 lymphopenia. The most common TEAEs were insomnia (50%), fatigue (30%), arthralgia (20%), back pain (20%), lymphopenia (20%), and nausea (20%). BGB-11417 exposure increased dose-dependently from 80 mg to 320 mg with high interpatient PK variability. BGB-11417 exposures after single and multiple doses appeared similar, indicating limited accumulation. Conclusion(s): BGB-11417 plus dexamethasone was generally well-tolerated in patients with R/R MM harbouring t(11;14) at doses <=640 mg. Efficacy data are forthcoming. Recruitment is ongoing in the US, Australia, and New Zealand;the BGB-11417, dexamethasone, and carfilzomib combination arm will open in the future.
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Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug candidate for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor of drug transporters P-glycoprotein, breast cancer resistant protein (BCRP) and organic anion transporting polypeptide 1B1 (OATP1B1). Ph 1 studies in healthy participants were conducted to assess the clinical implications of these results using digoxin (DIG) and rosuvastatin (ROSU) as P-gp and BCRP/ OATP1B1 index drugs, respectively. Method(s): Both studies employed a similar design with 2 groups of 14 healthy participants: Day 1/period 1, all participants received a single dose of DIG 0.25mg or ROSU 10mg alone. In period 2, participants received DIG 0.25mg or ROSU 10mg with BEM 1100mg, simultaneously (n=14) or staggered by 2h (n=14). Serial plasma samples were collected and quantitated for DIG or ROSU concentrations. Result(s): A single dose of BEM 1100mg simultaneously administered slightly increased the Cmax of DIG (78%), yet had no effect on its AUC, consistent with the transient nature of BEM plasma PK. When dosed staggered, BEM did not affect the PK of DIG. A single dose (simultaneous or staggered) of BEM 1100mg slightly increased the plasma exposure of ROSU (20%-40%). There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): A single high dose of BEM 1100mg only slightly increased the plasma exposure of the P-gp and BCRP/OATP1B1 index drugs DIG and ROSU. BEM has low potential to exhibit clinical meaningful inhibition of these transporters. No dose adjustment will be needed for drugs that are sensitive substrates of P-gp or BCRP/OAT1B1 when co-administered with BEM, staggered dosing may lessen any DDI risk.
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From March 2020 to May 2022, when SARS-CoV2 pandemic started spreading in Italy, 15 consecutive patients with non-Hodgkin Lymphoma (NHL) have been treated at the Pediatric Unit of Fondazione IRCCS Istituto Nazionale dei Tumori. Three of 15 patients developed COVID19 while on treatment [1 Burkitt lymphoma (BL), 1 anaplastic large cell lymphoma, 1 lymphoblastic T-cell lymphoma (T-LL)] and one patient at diagnosis [gray zone lymphoma (GZL), previously misdiagnosed as Hodgkin lymphoma]. Median age at diagnosis was 12 years;3 were male. Median positivity time of the nasal swab was 58 days (range 9-107 days). All patients remained asymptomatic or paucisymptomatic (flu-like symptoms) while positive. The first positive patient with T-LL, was in the induction phase of the Euro-LB-02 protocol guidelines: he succeeded in completing the whole treatment during the 107 days of swab positivity, experiencing mild toxicities (grade 2 transaminases and grade 3 lipase increase, both reversible) without significant delays. For this reason, we reduced the total dose of the first HD-MTX (protocol M) and administer the subsequent doses in 6 hours infusion instead of 24 with no further toxicities. After this first experience, all the subsequent patients have been treated accordingly, without major deviations from the established protocols. Minor precautions: the patient with refractory GZL received IEP course instead of IGEV as second-line treatment to avoid severe subsequent immunosuppression;the patient with BL omitted the fourth course of Rituximab during the period of swab positivity. Overall, we did not observe outstanding toxicities except for a toxic MTX level with subsequent reversible acute renal failure. Main teaching from these pilot experiences, which may translate into guidelines: 1) SARS-CoV2 infection is not an absolute contraindication to the oncological treatments. This is of main importance for the patients affected by lymphoma whose dose-intensity has a prognostic value. 2)We need to pay caution during HD-MTX treatment;indeed, we observed unexpected similar toxicities in other patients treated with HD-MTX for other solid malignancies. 3) The clearance of SARS-CoV2 might be exceptionally prolonged with persistent positivity of the nasal swabs for a longer time than the matched healthy population due to the immunosuppression characterizing lymphoma patients. For this reason and given the importance of maintaining the dose-intensity, specific treatments aiming at speeding up the clearing process are warmly suggested. (Figure Presented) Figure 1: (: 091) ITHACA study design and blood sampling time points. (OHT = Orthotopic Heart Transplant).Copyright © 2022 Elsevier Ltd. All rights reserved.
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Effective drug delivery to the brain is critical for the treatment of glioblastoma (GBM), an aggressive and invasive primary brain tumor that has a dismal prognosis. Radiation therapy, the mainstay of brain tumor treatment, works by inducing DNA damage. Therefore, inhibiting DNA damage response (DDR) pathways can sensitize tumor cells to radiation and enhance cytotoxicity. AZD1390 is an inhibitor of ataxia-telangiectasia mutated kinase, a critical regulator of DDR. Our in vivo studies in the mouse indicate that delivery of AZD1390 to the central nervous system (CNS) is restricted due to active efflux by P-glycoprotein (P-gp). The free fraction of AZD1390 in brain and spinal cord were found to be low, thereby reducing the partitioning of free drug to these organs. Coadministration of an efflux inhibitor significantly increased CNS exposure of AZD1390. No differences were observed in distribution of AZD1390 within different anatomic regions of CNS, and the functional activity of P-gp and breast cancer resistance protein also remained the same across brain regions. In an intracranial GBM patient-derived xenograft model, AZD1390 accumulation was higher in the tumor core and rim compared with surrounding brain. Despite this heterogenous delivery within tumor-bearing brain, AZD1390 concentrations in normal brain, tumor rim, and tumor core were above in vitro effective radiosensitizing concentrations. These results indicate that despite being a substrate of efflux in the mouse brain, sufficient AZD1390 exposure is anticipated even in regions of normal brain. SIGNIFICANCE STATEMENT Given the invasive nature of glioblastoma (GBM), tumor cells are often protected by an intact blood-brain barrier, requiring the development of brain-penetrant molecules for effective treatment. We show that efflux mediated by P-glycoprotein (P-gp) limits central nervous system (CNS) distribution of AZD1390 and that there are no distributional differences within anatomical regions of CNS. Despite efflux by P-gp, concentrations effective for potent radiosensitization are achieved in GBM tumor-bearing mouse brains, indicating that AZD1390 is an attractive molecule for clinical development of brain tumors.Copyright © 2022 American Society for Pharmacology and Experimental Therapy. All rights reserved.
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The proceedings contain 68 papers. The topics discussed include: post-transplant lymphoproliferative disorder (PTLD) in a patient with rheumatoid arthritis;cancer, covid and control of RA - a toxic combination?;continuation of golimumab (anti-TNF) in a patient with SpA and low-risk prostate cancer, what is the right decision?;orbital lymphoma in a 72-year-old lady with rheumatoid arthritis: an argument for rituximab;a case of cancer mimicking inflammatory arthritis;managing relapsing and refractory lupus nephritis in juvenile systemic lupus erythematosus: a case report;a case of juvenile systemic lupus erythematosus with pyrexia of unknown origin;recurring brachial plexopathy- the zebra among the horses;and Neisseria meningitidis as a cause of isolated bilateral polyarticular native knee joint septic arthritis.
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The proceedings contain 68 papers. The topics discussed include: post-transplant lymphoproliferative disorder (PTLD) in a patient with rheumatoid arthritis;cancer, covid and control of RA - a toxic combination?;continuation of golimumab (anti-TNF) in a patient with SpA and low-risk prostate cancer, what is the right decision?;orbital lymphoma in a 72-year-old lady with rheumatoid arthritis: an argument for rituximab;a case of cancer mimicking inflammatory arthritis;managing relapsing and refractory lupus nephritis in juvenile systemic lupus erythematosus: a case report;a case of juvenile systemic lupus erythematosus with pyrexia of unknown origin;recurring brachial plexopathy- the zebra among the horses;and Neisseria meningitidis as a cause of isolated bilateral polyarticular native knee joint septic arthritis.
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Background: Extra-nodal natural killer/T-cell lymphoma (NKTCL) is a rare form of non-Hodgkin lymphoma (NHL). Few cases of Ocular adnexal T-cell lymphoma presenting as pre-septal cellulitis/orbital cellulitis has been reported in the literature. However, Extra Nodal NK/T cell non-Hodgkin lymphoma presenting as orbital cellulitis and also with multisystem involvement in the paediatric age group is a rare presentation and not reported earlier. Method(s): 13 years old male presented to us with weakness of left side with left facial palsy for 2.5 months and right eye severe proptosis and vision loss for 2 months. Initially, He was diagnosed with Orbital cellulitis and treated for the same from elsewhere. PET-CT showed FDG avid metabolic active largest soft tissue mass in left lung upper lobe encasing first rib, large active soft tissue mass in the periorbital area, right nasal cavity, right lobe of the thyroid, right kidney, pancreas head, scrotal area, multiple bony lesions. Further biopsy from rib mass revealed NK- T cell lymphoma. He was diagnosed with a rare case of NK/ T cell Non-Hodgkin Lymphoma with multisystem involvement. Initially, he responded to SMILE regimen of chemotherapy, but he developed white fluffy vitreous opacities in the left eye after 3 cycles, and before vitreous biopsy, he contracted COVID 19 infection. During COVID treatment he has received IV antibiotics and steroids. After recovery from covid illness, his vitreous opacities got disappeared suggestive of possible endophthalmitis rather than intraocular lymphoma. Later within two weeks, he succumbed to the disease. Result(s): Died with disease Conclusion(s): Our case highlights that ocular adnexal lymphoma can be a possible masquerade in cases of refractory lid swelling with erythema and induration and can present as orbital cellulitis with multisystem involvement. Copyright © 2022
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Background Clonal hematopoiesis (CH) is an age-related phenomenon characterized by the overrepresentation of blood cells arising from a single, mutant clone and is detectable in 10-20% of individuals over 70.1 CH has now been implicated in a variety of non-hematological disorders, such as cardiovascular diseases and Covid-19 infections, by exacerbating the innate inflammatory response.2-4 However, the impact of CH in solid tumors and response to immune checkpoint blockade (ICB) is unknown. Methods To assess the prevalence and role of CH in patients with solid tumors, we analyzed publicly available data from the MSKCC-IMPACT study.5, 6 To mechanistically study CH in solid tumors, we established an orthotopic model of pancreatic adenocarcinoma (PDAC) in mice with Tet2+/- CH. CH and WT mice were treated with either ICB (aCTLA-4 + aPD-1) or vehicle control. Single-cell (sc-) RNAseq was performed on tumor infiltrating lymphocytes (n=3/group) while remaining mice were observed for disease progression and overall survival (n=10/group). Results Analyzing CH frequencies in a cohort of patients with solid tumors, we observed that the prevalence of CH was approximately 5 times higher in patients with cancer when compared to healthy age-matched controls. Further, patients with detectable CH clones had significantly worse overall survival (figure 1A). In vivo, sc-RNAseq data revealed that myeloid cells present within the pancreatic tumors of mice with Tet2+/- CH were significantly enriched for both type I and type II interferon (IFN) signaling (figure 1B). Further, these IFN+ myeloid cells were ablated after ICB therapy in Tet2+/+ WT mice but persisted in mice with Tet2+/- CH (figure 1C). PDAC tumors from mice with Tet2+/- CH had approximately half the total number of infiltrating CD8 T cells at baseline when compared to those from Tet2+/+ WT mice. Upon ICB treatment, CD8 effector cells only expanded in the tumors from Tet2+/+ WT mice. Functionally, this translated to more rapidly progressing tumors, resistance to ICB, and reduced overall survival in mice with Tet2+/- CH (figure 1D). Conclusions CH is present in upwards of 30% of patients with solid tumors and is associated with significantly worsened prognosis. Modeling PDAC in the presence of Tet2+/- CH in vivo revealed distinct alterations in the tumor microenvironment that ultimately influenced tumor progression and response to ICB. This proposed research bridges the fields of solid tumor immunology and clonal hematopoiesis to address novel mechanisms of immunotherapy resistance that will span cancer type and, ultimately, improve patient care.
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Background: Despite of the administration of multiple doses of vaccines (vax), cancer patients (pts) are a group at high risk of COVID-19 complications. The aim of this study is to evaluate the factors associated with the humoral response to the 3rd dose (D) of mRNA-based vax in cancer pts during or after active treatment. Patients and Methods: Single institution, prospective study conducted at the L. Sacco Hospital, Milan, between 5/2021-4/2022. 30 days after the 2nd and 30 days after the 3rdD of BNT162b2 or mRNA-1273 (selected based on local pharmacy availability), seric levels of 3 antibodies (Ab) were measured in solid tumors pts during or after the active treatment, by a fluorescence bead-based assay. Anti-S and anti-RBD IgG to determine the humoral response to vax, anti-N IgG to identify a previous exposure to SARS-Cov-2. Primary objective: to assess the seroconversion (SC) rate and the Ab titres after 3rdD. Secondary Objectives: to detect any relation between the 3rdD response and pre-defined pts variables;to evaluate the humoral response to 3rdD in pts not responding to the 2ndD. Result(s): 99 of 110 pts were evaluated: 67.7% female, median age 63 ys, 49.5% breast cancer, 67.7% advanced stage. Active treatment: 40.4% biologic agent, 23% chemotherapy (alone or combination), 11.1% hormone. 3rdD vax type: 74.8% BNT162b2, 25.2% mRNA-1273. SC after 3rdD was obtained in 99% of pts. The use of GCSF was associated with a lower amount of anti-RBD IgG (p=0.03). A 6 vs 5 months interval between 2nd and 3rdD was correlated with higher anti-S IgG level (p<0.001). The heterologous vax regimen was associated with higher rate of anti-S IgG (p=0.04), especially the sequence mRNA- 1273 x 2 -> BNT162b2 (p=0.001). No significant correlation at the multivariate analyses was found between Ab levels and the other variables tested (age, BMI, cancer type, tumor stage, use of steroids, previous exposure to SARS-CoV-2, anti-cancer therapy, neutropenic potential of the therapy). 21/22 pts not responding to the 2ndD obtained SC after 3rdD. Conclusion(s): 3rdD of anti-COVID-19 vax is effective in cancer pts with solid tumors undergoing or after recent treatment. In this group the 3rdD oversteps all the negative influence of the factors related to the 2ndD vax failure, achieving the same response of the healthy population and demonstrating efficacy in not previously responders, too. The better performance of the heterologous vax regimen could be due to an exposition to a wider range of epitopes.
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The world population is getting older, but a great challenge is how to increase health span and not only lifespan. What is the role of genetics versus environment? Several recent breakthroughs such as the human genome project, the IPS stem-cells and the CRISPR technology for gene editing will allow a revolution in gene therapy, precision and regenerative medicine and xenotransplantation. Aiming to contribute to a healthier longevity, our group is developing several projects including the characterization of the genome of our elderly highly admixed population. We have performed whole genome sequencing of about 1500 healthy Brazilians older than 60, which represents the largest genome databank in Latin America. Our aims were a) to have a database from our population in order to improve the interpretation of pathogenicity of rare unknown variants in patients with undiagnosed genetic disorders and precision medicine b) identify “protective” variants underlying healthy longevity. We found 2 million genetic variants which were not present in the international databanks (Naslavsky et al., 2022). Since the advent of COVID-19 pandemic, we are investigating genetic variants in individuals, who were exposed to SARS-Cov-2 and remained asymptomatic. To address this question, we investigated discordant couples where one was infected and develop COVID-19 while the partner remained asymptomatic and serum negative. We collected samples from nonagenarians and centenarians who survived COVID-19 or remained asymptomatic. We will infect different IPS derived cell lines from “resistant” centenarians with SARS-Cov2 in an attempt to increase our understanding on “resistant genetic variants and mechanisms”.
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Genome instability mechanisms that characterize cancer initiation and subsequent therapy resistance are still less well understood. Recent evidence suggests that the REV1-dependent translesion synthesis (TLS) is the cornerstone for new mutation formation that primes genome instability, including intrinsic and acquired resistance to therapy. Remarkably, REV1 inhibition also switches the biology of cisplatin-dependent cell death response from apoptosis to senescence, suggesting that REV1 functions beyond a DNA damage polymerase. Furthermore, we discovered two unexpected phenotypes of REV1 TLS polymerase: a) REV1 inhibition triggers autophagy that associated with radioresistance. b) By means of striking preliminary data we show that REV1 inhibition limits SARS-CoV-2 RNA virus propagation, which we recently reported to cause hostcell DNA damage response and telomere instability. These new observations add to the repertoire of REV1- dependent genome instability pathways significant to understanding a wide repertoire of human diseases, including cancer pathogenesis.
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Background: RET fusions are found in 1-2% of patients (pts) with advanced non-small cell lung cancer (aNSCLC). Targeted therapy with RET inhibitors (RETi) significantly improved prognosis. Molecular mechanisms of resistance are still incompletely characterized. Methods: This multicentric retrospective study included 24 centres. Eligible pts had a RET+ aNSCLC, were treated with a RETi and had at least one molecular profile by next-generation sequencing (NGS), performed before and/or after RETi, on tissue and/or plasma samples. Primary resistance under RETi was defined as disease progression (PD) within 6 months of therapy. Results: 95 patients were included with 112 biopsies: 93 at baseline, 19 at PD. 17 patients had paired NGS (baseline and PD). Median age was 65 years (range 56-72);62% were female, 54% were never smokers, 17% had brain metastasis (BM) at diagnosis. 55 patients received pralsetinib, 36 selpercatinib, 4 other RETi. Overall, median PFS under RETi was 17.1 months (95%CI 12.6-28). Primary resistance to RETi occurred in 22 (23%) patients. Primary resistant versus durable responders to RETi had non-adenocarcinoma histology in 9% vs 46% (p=0.61), smoking history in 57% vs 40% (p=0.21), BM in 5% vs 21% (p=0.1), TP53 mutations in 37% vs 22% (p=0.23). KRAS G12V mutation and SMARCA4 alterations were found only in poor responders (4.5% vs 0%, p=0.2;and 25% vs 0%, p=0.04, respectively). Among biopsies at PD (N=19, 13 liquid and 6 tissue biopsies), 7/13 (54%) liquid biopsies failed due to insufficient ctDNA. In 12 evaluable pts, 3 (25%) acquired secondary RET mutations (2 G810S and 1 S904F), 3 (25%) had novel RET rearrangements (2 in intron 11, 1 RET-DOCK1, 1 RET-CSGALNACT2) and 3 (25%) pts had off-target alterations (2 MET and 1 MYC amplification). Three pts (25%) developed novel TP53 mutations, while 3 (25%) had no novel identifiable alterations at PD. Conclusions: SMARCA4 and KRAS co-mutations may have a role in primary resistance to RETi. Secondary RET mutations, novel RET rearrangements and MET/MYC amplifications were identified after treatment with RETi. More than half of pts had insufficient ctDNA at PD, making tissue biopsy essential to identify resistance mechanisms. Legal entity responsible for the study: Institut Gustave Roussy. Funding: Has not received any funding. Disclosure: V. Fallet: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Takeda, Roche, Pfizer, Sanofi, Sandoz, Jansen;Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Takeda, Pfizer, MSD;Financial Interests, Personal, Expert Testimony: GSK, Boehringer. C. Audigier-Valette: Financial Interests, Personal, Advisory Role: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Eli Lilly, Novartis, Pfizer, and Roche. A. Russo: Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, MSD, Novartis;Financial Interests, Personal, Writing Engagements: AstraZeneca, Novartis. A. Calles Blanco: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Lilly, Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Takeda, Sanofi;Financial Interests, Personal, Other, Speaker honoraria: Bayer;Financial Interests, Institutional, Research Grant, Drug-only for Investigator-initiated trial: Merck Sharp & Dohme. P. Iranzo Gomez: Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb Recipient, F. Hoffmann, La Roche AG, Merck Sharp & Dohme, Boehringer Ingelheim, MSD Oncology, Rovi, Yowa Kirin, Grunenthal Pharma S.A., Pfizer. M. Tagliamento: Financial Interests, Personal, Other, medical writer: Novartis, Amgen;Financial Interests, Personal, Invited Speaker, travel/accommodation: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. C. Lindsay: Financial Interests, Institutional, Principal Investigator: Roche, Amgen, BI;Financial Interests, Personal, Advisory Role: CBPartners, Amgen. S. Ponce: Financial Interests, Institutional, Principal Investigator: Merck Sharp and Dohme, F. Hoffmann-La Roche, Foundation Medicine, PharmaMar. Personal fees: Merck Sharp and Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche, Foundation Medicine, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Pfizer, Amgen, Celgene.;Financial Interests, Personal, Advisory Board: Merck Sharp and Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche, Foundation Medicine, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Pfizer, Amgen, Celgene.;Non-Financial Interests, Personal, Other: Merck Sharp and Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche. M. Aldea: Financial Interests, Personal, Invited Speaker, travel/accommodation: Sandoz. All other authors have declared no conflicts of interest.
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Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. Approximately 2% of patients with CLL develop immune thrombocytopenic purpura (ITP) during the course of the disease. When resistant to steroids, this constitutes as indication for treatment of the CLL. Here we report a patient with refractory ITP secondary to CLL successfully treated with venetoclax. Aims: To present an interesting case with CLL related refractory ITP treated successfully with novel agent venetoclax. Methods: Patient data was taken from the patient herself and Hospital records. Informed consent to publish the case is obtained from patient. Permission for off-label venetoclax and eltrombopag was obtained from Ministry of Health of Turkey. Results: 46-year-old female patient presented with lumps on her neck that were present for the last 9 months in November 2020. She has a history of frequent pneumonia and otitis but no constitutional symptoms. Her physical examination reveals multiple 2cm lymphadenopathies on her neck and no organomegaly or other pathological features. Blood work shows mild lymphocytosis (6800/mm3) with no serious cytopenias. Peripheral blood smear, flow cytometry and bone marrow biopsy were all compatible with CLL. She was classified as Binet A CLL and was followed up with no treatment after appropriate vaccinations against capsulated pathogens. In July and August 2021 she received two doses of mRNA vaccination against COVID-19. On 1st November 2021 she experienced excessive menstrual bleeding and blood work showed platelet count of 23000/mm3, she was started on steroids (1 mg/kg/day) and after 4 days platelet count has risen to 55000/mm3, she discontinued steroids on her own against medical advice. On 13th of November she presented with extensive petechiae and purpura and was again started on steroids and was given the courses of intravenous immunoglobulins (IVIG) without any sustained response. She was refractory to platelet transfusions too. She was transferred to our clinic. She was found to have del11q and del13q. She refused bone marrow examination. She was treated with rituximab, steroids, vincristine, IVIG and eltrombopag for ITP without success (Fig. 1). She had a minimal response to IVIG only. She received two courses of bendamustine (90 mg/kg for two days) also without success. Three courses of plasmapheresis yielded no response either. After mild success with immunadsorbtion apharesis she was started on venetoclax plus rituximab with ramp-up. Sustained response was achieved within the first week of venetoclax therapy. (Figure Presented ) Summary/Conclusion: Gordon et al. reported 2 CLL cases one with ITP and other with Evans syndrome successfully treated with venetoclax. We think, this treatment should be considered in patients with refractory immune cytopenias secondary to CLL and assessed with prospective clinical trials.
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Background: Lenalidomide (LEN) maintenance and continuous LEN-based induction therapy until disease progression have become standard of care for frontline therapy of multiple myeloma (MM). As such, an increasing number of patients (pts) in need of 2nd line therapy have LEN-refractory disease. Optimal treatment in this setting has not been rigorously assessed in randomized studies. The phase I portion of Alliance A061202 demonstrated the safety of the ixazomib-pomalidomide-dexamethasone (IXA-POM-DEX) combination for the treatment of pts with LEN and proteasome inhibitor (PI)-refractory MM. Aims: In the randomized phase II portion, we evaluated the addition of IXA to POM-DEX for PI naïve / sensitive pts progressing on LEN as part of 1st line therapy. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), depth of response, survival and safety. Methods: Pts were randomized 1:1 to IXA-POM-DEX or POM-DEX and stratified by prior bortezomib exposure, International Staging System stage (1 and 2 vs 3) and the presence of high-risk cytogenetics. POM was administered at 4 mg on days 1-21;IXA 4 mg on days 1, 8 and 15;and DEX 20 mg (>75 years (yrs)) or 40 mg (≤75 yrs) on days 1, 8, 15 and 22 of a 28-day cycle. Treatment was continued until disease progression, the emergence of unacceptable side effects or withdrawal of treatment consent. Results: 38 and 39 eligible pts were assigned to IXA-POM-DEX and POM-DEX, respectively. The median age was 66 yrs (range 41-83) and 64 yrs (range 52-85). A planned first interim analysis was conducted after 43 out of 57 required events had occurred. PFS favored the IXA-POM-DEX arm (one-sided log rank test value = 4.6345, p=0.03134 [< p-value boundary of 0.058]), yielding a hazard ratio of 0.528 (upper 90% bound = 0.777). A stratified log-rank test found that PFS was superior for the triplet after adjusting for stratification factors (one-sided stratified log rank test value = 5.8371;p=0.0157), adjusted hazard ratio 0.451 (upper 90% bound = 0.694). The ORR favored IXA-POM-DEX (63.2% vs 43.6%, p=0.0853), and the ≥very good partial response was 26.3% vs 5.1%, respectively (p=0.01). The clinical benefit rate (ORR + minimal response rate) was 73.7% and 56.4%. The most common grade 3/4 adverse events included lymphopenia, neutropenia, anemia, and fatigue in 40%, 37%, 16% and 16% of IXAPOM-DEX-treated pts and 26%, 21%, 13%, and 15% of POM-DEX-treated pts. Therapy was discontinued for disease progression in 47.4% of pts on IXA-POM-DEX and 76.9% of pts on POM-DEX and for adverse events in 7.9% and 7.7% of pts, respectively. Summary/Conclusion: The addition of IXA to the POM-DEX backbone improved the depth of response and PFS for pts relapsing on LEN as part of 1st line therapy. Hematologic toxicity was increased with the addition of IXA, but side effects were manageable. The ease of administration of this all-oral combination allowed for safer, uninterrupted treatment during the COVID pandemic. Our results should be confirmed in phase III trials but lend support for this regimen as part of 2nd line therapy for this patient population.
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Background: The introduction of venetoclax into clinical practice has improved the outcome of patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL). The results of the MURANO trial published in March 2018 showed significantly longer progression-free survival (PFS) and overall survival (OS) in RR-CLL patients treated with venetoclax and rituximab (VEN-R) comparing to bendamustine and rituximab (BR) and resulted in the approval of VEN-R in the therapy of RR-CLL in the European Union and the United States. It should be noted that the results of registration studies often do not correspond with the data from real-life observations. Aims: To study the clinical efficacy and safety profile of VEN-R treatment in RR-CLL patients outside clinical trials. Methods: We performed retrospective analysis of RR-CLL patients treated with VEN-R in hematology centers of the Polish Adult Leukemia Study Group (PALG) from 2019 to 2021. Results: Clinical data of 117 RR-CLL patients treated with VEN-R were collected. Median patient age upon initiation of VEN-R therapy was 67 years (range 33 - 84 years). Seventy-two patients (61.5%) were men. Median Cumulative Illness Rating Scale (CIRS) was 6 (range 2 -16). Patients were treated with a median of 2 (range 1-9) previous lines of therapy, whereas 32 patients (27.4%) had relapsed following the first line of treatment. Overall, 25 patients (21.4%) had 17p deletion, whereas TP53 mutation was identified in 13 patients (11.1%). The median follow-up was 9.96 months (range 0.27 -29.13). The overall response rate (ORR) was 95.2%. Seventeen patients (14.5%) achieved complete remission (CR), 83 (70.9%) partial remission (PR), while in 5 patients (4.3%) disease progression was noted. In the patients with 17p deletion (n=22) or TP53 mutation (n=11), CR and PR were observed in 4 (12.1%) and 29 (87.9%) patients, respectively. The median PFS in the whole cohort was 20.8 (95% CI 18.43 -not reached) months and the median OS was not reached. In our study none of the analyzed clinico-pathological factors had significant impact on ORR, PFS and OS. During the follow-up time four (3.4%) cases of Richter transformation were diagnosed. There were 18 deaths recorded during the course of observation;3 (16.7%) due to disease progression and 7 (38.9%) due to COVID-19 infection. The others were due to infections other than SARS-CoV-2 (n=3, 16.7%) and the cause of death could not be specified in five cases (27.8%). Eighty-three patients (70.9%) remain on treatment, while treatment was discontinued in thirty-four cases (29.1%). Reasons for therapy discontinuation included patient's death (52.9%), treatment-related cytopenias (17.6%), disease progression (14.7%), Richter's transformation (11.8%), autoimmune hemolytic anemia (5.9%), diarrhea (2.9%) and infections (8.8%). In one case treatment discontinuation was due to consent withdrawal and one patient was lost to follow-up. The following adverse events of VEN-R treatment were reported during the study: all grade neutropenia (71.8% with grade 3/4 in 55.6%), anemia (51.3%), thrombocytopenia (47%), pneumonia (9.4%), neutropenic fever (6.8%), autoimmune hemolytic anemia (4.3%), immune thrombocytopenic purpura (1.7%), diarrhea (4.3%) and in one case exacerbation of heart failure was observed. Summary/Conclusion: In this retrospective analysis the outcomes of treatment with the VEN-R regimen in real-life setting were worse than those reported in the MURANO trial.
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Background: We have previously described AUTO1, a CD19 CAR with a fast off-rate CD19 binding domain, designed to reduce CAR T-cell immune toxicity and improve engraftment. Its clinical activity has been tested in r/r paediatric and adult B-ALL (Ghorashian S et al., Nat Med 2019;Roddie C et al., JCO 2021). This data confirms the intended function of the receptor, with low levels of CRS/ICANS and long-term engraftment of CAR T-cells observed in both patient groups. Aims: We have initiated testing of AUTO1 in the setting of B-NHL and CLL/SLL (NCT02935257). Methods: Manufacturing: CAR T-cell products were generated using a semi-automated closed process from non-mobilised patient leukapheresate. Study design: Subjects ≥ 16y underwent lymphodepletion with fludarabine (30mg/m x3) and cyclophosphamide (60mg/kg x1) prior to AUTO1 infusion, with the exception of the DLBCL cohort who additionally received a single dose of pembrolizumab (200mg) on day -1 to potentiate CAR-T expansion. AUTO1 dose varies based on the indication. Split dosing of 230 x106 CD19 CAR T-cells at day 0 and day 9 is employed in the CLL cohort. A single dose of 200 x106 CD19 CAR T-cells is delivered to patients with B-NHL. Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months. Results: As of 8th February 2022, we enrolled 23 patients: 11 low grade NHL (LG-NHL:7 with FL and 3 with MCL), 7 DLBCL and 5 CLL. Apheresis was successful in all 23 patients and product manufacture was successful in 22 (pending in the last). 19 patients were infused: 10 with LG-NHL, 6 with DLBCL and 3 with CLL. 1 CLL patient was pending infusion at time of data cut-off and 2 patients died pre-infusion: 1 MCL patient, from COVID-19 and 1 CLL patient, from intracerebral haemorrhage. Patients treated with AUTO1 had a median age of 60 years (range 39-79), had received a median of 3 prior lines of treatment (range 2-8). Grade 1 CRS was reported in 6/19 and Grade 2 CRS in 3/19. No ICANS was observed in the B-NHL and CLL cohorts. CAR engraftment was observed in 13/13 patients evaluated by qPCR with ongoing persistence in 12/13 patients at last follow-up. In the LG-NHL and DLBCL cohorts 10/10 and 4/5 evaluable patients respectively were in CMR by 18FDG PET-CT post-treatment. Responses were ongoing in 9/10 LG-NHL at 12 months and in 4/4 DLBCL at months 1, 3, 3 and 6. In the CLL cohort, 2/3 evaluable patients achieved MRD negative remission in the bone marrow with residual small volume lymph nodes by CT at 6 and 3 months of follow-up respectively. 1 CLL patient did not engraft and had SD at month 1. Summary/Conclusion: AUTO1 has a tolerable safety profile in patients with r/r B-NHL and CLL despite high disease burden. Early data shows excellent complete remission rates and excellent CAR engraftment/expansion. Additional patients, updated data and longer follow up will be presented.