Previous Regimens Research Articles

Targeting an elevated FVIII level using personalized rurioctocog alfa pegol prophylaxis in specific patient populations with hemophilia A: post hoc subanalysis of the randomized, phase 3 PROPEL study.

The phase 3, prospective PROPEL study demonstrated that pharmacokinetic (PK)-guided prophylaxis targeting elevated factor VIII (FVIII) troughs in patients with hemophilia A resulted in lower annualized bleeding rates (ABRs) and a higher proportion of patients experiencing zero bleeds in the second 6 months of treatment when targeting a FVIII trough of 8-12% versus 1-3%. To investigate the benefit of PK-guided prophylaxis with rurioctocog alfa pegol targeting two FVIII trough levels in specific patient subgroups in a post hoc analysis using data from PROPEL. This is a post hoc analysis of data from the PROPEL study. The design and primary outcomes of the prospective, randomized PROPEL study (NCT02585960) have been reported previously. This post hoc analysis reports data stratified by FVIII half-life (t1/2), hemophilic arthropathy status, number of target joints at screening, previous treatment regimen, and ABR range in the 12 months before study entry. Targeting an elevated FVIII trough of 8-12% was associated with higher average FVIII levels over time, regardless of FVIII t1/2 at baseline. The decrease in total ABR between the 8-12% and 1-3% arms was greatest in patients with a FVIII t1/2 of 6 to <12 h (0.7 versus 3.5); a higher number of target joints, that is, at least four target joints, at baseline (0.2 versus 1.6); the presence of arthropathy (0.1 versus 1.7); and those previously treated on-demand (0.3 versus 1.8). These results support the feasibility of targeting elevated FVIII levels using personalized rurioctocog alfa pegol prophylaxis. These benefits may be especially important in patients with a short FVIII t1/2 and those receiving standard prophylaxis with frequent breakthrough bleeds, arthropathy, and target joints. ClinicalTrials.gov Identifier: NCT02585960; https://clinicaltrials.gov/ct2/show/NCT02585960.

Off-Label Uses of Ranibizumab and Aflibercept for Age-Related Macular Degeneration in Turkey.

To evaluate the clinical and demographic aspects of off-label drug use applications for age-related macular degeneration (AMD) in Turkey. Applications for off-label drug use in the treatment of AMD to the Turkish Medicines and Medical Devices Agency (TITCK) in 2018 were retrospectively analyzed. Demographic characteristics, requested drugs, previous treatment regimens, and reasons for applications were evaluated. The mean age of the patients (n = 209) was 64.9 ± 15.7 years, of which 48.8% were male and 51.2% were female. Ranibizumab (n = 113) comprised 54.1% and aflibercept (n = 96) 45.9% of off-label use applications. No application was made for bevacizumab. The most frequent reasons for application were switchback (49.3%), nonreimbursement of indicated drugs in cases under 50 years of age (24.4%), and failure to complete the loading dose (14.4%). Ranibizumab was the most requested off-label drug for AMD. There was no application for off-label bevacizumab since its use does not require approval from TITCK. In Turkey, new rules were established for the reimbursement of intravitreal drugs for AMD in 2019. Three doses of intravitreal bevacizumab were required initially for aflibercept and ranibizumab to be covered for reimbursement. There is not enough data in the English literature regarding the off-label use of ranibizumab and aflibercept for AMD. This study provides information about drug regulations and the off-label treatment options preferred by physicians for AMD in Turkey.

Interventional study on Dolutegravir and other antiretrovirals in patients with subclinical atherosclerosis in the Kinshasa Hospital

After 2016, the World Health Organization (WHO) proposed Dolutegravir (DTG) as an alternative first-line treatment for adults. Thus, the purpose of this study was to identify biomarkers of cardiometabolic risk capable of demonstrating the beneficial effect of Dolutegravir (DTG) compared to other antiretrovirals in predicting atherosclerosis in people living with HIV (PLHIV) and hospitalized in Kinshasa Hospital. we conducted an interventional study of people living with HIV who had received antiretroviral therapy (ART) for at least 6 months and were treated in the structures of the network coordinated by the Catholic Church (BDOM-Bureau Diocésain des Oeuvres Médicales) and of the University Clinics of Kinshasa (CUK) between January 2017 and December 2021. Subclinical atherosclerosis was defined as Pulsed Pressure (PP) ≥60 mm Hg; Carotid Intima-Media Thickness (CIMT) > 0.8 mm; and Systolic Pressure Index (SPI) < 0.9. Logistic regression was used in the statistical analysis of associations. a total of 334 PLHIV were recruited, of whom 96.1% (n=321) were on ART and 13.9% (n=13) were ART naïve patients. The mean age of PLHIV was 51±12 years with a female predominance (70.4%; n=235); the independent determinants of subclinical atherosclerosis were marital status (aOR: 4. 95% CI 1.5-10.5; p<0.006), low socioeconomic level (aOR: 10.7, 95% CI 2.3-48.7 p<0.002), duration of HIV infection (aOR: 6.6, 95% CI 2.8-16; p<0.0001), duration of antiretroviral therapy ≥9 years (aOR: 0.3, 95% CI 0.2-0.7; p<0.005) and total cholesterol ratio/high-density lipoprotein-cholesterol (CT/HDL-c)(aOR: 2, 95% CI 1.1-3.6; p= 0.034). The mean values of traditional and emergent variables were significantly higher in the previous ART regimen without DTG than in the new regimen with DTG. However, dyslipidemia was detected during the new DTG-based regimen. dyslipidemia was common during the DTG-based regimen. Marital status, low socioeconomic level, duration of HIV infection, duration of antiretroviral treatment beyond 9 years and the TC/HDL-c ratio were identified as determinants of subclinical atherosclerosis in PLHIV on ART hospitalized in the Kinshasa hospital.

Multi-Phenotypic Breast Cancer Post-Radiotherapy for Hodgkin Lymphoma: A Case of Secondary Malignancy.

Morbidity and mortality associated with radiation-induced secondary malignancies (RISMs) have shifted treatment paradigms to minimize or eliminate radiation from treatment regimens. In this case, a 48-year-old woman was diagnosed with Hodgkin lymphoma (HL) and treated with radiotherapy in 2000. In 2018, she was diagnosed with ductal carcinoma in situ (DCIS) of the right breast and treated with a mastectomy. Soon after, she developed triple-negative invasive ductal carcinoma (IDC) in her reconstructed breast. The patient underwent a left lumpectomy, and pathology showed ER-/PR-/HER2+ IDC. This patient's multi-phenotypic DCIS and IDC presentation are suspected to be RISM due to her previous HL treatment regimen.

Safety and Efficacy of Trifluridine/Tipiracil Administered After Anti-PD-1 Therapies for Advanced Gastric Cancer.

The phase III TAGS trial of trifluridine/tipiracil showed a survival benefit compared with placebo as a third- or later-line treatment in patients with advanced gastric cancer (AGC), in which only a few patients had a history of previous treatment with immune checkpoint inhibitors. We retrospectively reviewed consecutive patients with AGC who received trifluridine/tipiracil monotherapy as third- or later-line chemotherapy at our institution. Clinical outcomes were assessed in both overall population and patients with previous anti-PD-1 therapies. A total of 60 patients were included in this study. Eastern Cooperative Oncology Group performance status was 0, 1, and 2 in 37%, 52%, and 12% of patients, respectively. Median number of previous treatment regimens was 4 (range=2-7). Forty-nine (82%) patients had previously received anti-PD-1 therapies. In the overall population, the most common grade 3 or higher treatment-related adverse events were neutropenia (37%), anemia (32%) leukopenia (20%), thrombocytopenia (8%), and anorexia (7%). The frequencies of grade 3 or higher events were not increased among patients with previous anti-PD-1 therapies, and no delayed onset immune-related adverse events occurred. In the overall population, objective response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS) were 4%, 42%, and 1.8 months, respectively. Efficacy results in patients with previous anti-PD-1 therapies (ORR 5%, DCR 47%, and median PFS 2.1 months) were almost comparable with those in the overall population. Trifluridine/tipiracil monotherapy after exposure to anti-PD-1 therapies showed manageable safety profile and anti-tumor activity in AGC patients.

How to Perform Intravesical Chemotherapy after Second TURBT for Non-Muscle-Invasive Bladder Cancer: A Single-Center Experience

The objective of this study aimed to explore whether the original IVC regimen should be continued after the second TURBT or whether the IVC induction phase should be restarted from the beginning. A retrospective analysis was performed on 137 patients who underwent a second TURBT at the Affiliated Hospital of Xuzhou Medical University between April 2014 and June 2022. Based on the pathological findings, patients were divided into two groups: group A patients, who did not have a residual tumor on pathological examination after the second TURBT; and group B patients, who had residual tumor. Recurrence was determined using cystoscopy and imaging every three months. The endpoint was recurrence-free survival. In the entire cohort, there was a statistically significant difference in the RFS between patients in the two IVC regimens (p = 0.029). The RFS of patients in group B1 was significantly lower than that of patients in group B2 (p = 0.009). There was no significant difference in RFS between the subgroups A1 and A2 (p = 0.560). Multivariate Cox regression analysis confirmed that the IVC regimen after a second TURBT (p = 0.012) and T stage after a second TURBT (p = 0.005) were both independent predictors for patient RFS. If the pathological findings of the second TURBT specimen is benign, patients can continue their previous treatment regimen without restarting an IVC induction phase. Unnecessary IVC can be avoided in these patients. In contrast, for patients with residual tumors in the second TURBT specimen, the need to restart the IVC induction phase should be emphasized to improve patient prognosis.

Adverse Events Associated with Encorafenib Plus Cetuximab in Patients with BRAFV600E-mutant Metastatic Colorectal Cancer: An in-depth Analysis of the BEACON CRC Study

BackgroundThe BRAF inhibitor encorafenib in combination with cetuximab was recently approved for patients with BRAFV600E-mutated (BRAFV600Emut) metastatic colorectal cancer (mCRC). Approval was based on positive results from the phase 3 BEACON CRC study in BRAFV600Emut mCRC patients who had progressed after 1–2 previous regimens. This analysis provides a detailed examination of the adverse events (AEs) of interest (AEIs) with encorafenib+cetuximab in the BEACON study to aid gastrointestinal oncologists, given the limited experience with this combination. Materials and MethodsAEIs, including dermatological AEs, arthralgia/myalgia, nausea/vomiting, diarrhea, abdominal pain, fatigue/asthenia and nephrotoxicity, were examined in the doublet therapy group. Clinical characteristics associated with these AEs, AE grade, time to onset and time to resolution were also studied. ResultsSafety analysis included 216/220 patients randomized to doublet therapy. The most commonly occurring AEI was dermatological toxicity (75.5%), followed by arthralgia/myalgia (56.0%) and fatigue/asthenia (56.0%). Other than nephrotoxicity (7 patients; 5/7 with Grade 3 or 4), most AEs were Grade 1 or 2. Most AEs were more common in women than men (nausea/vomiting, diarrhea, abdominal pain, dermatological AEs, and arthralgia/myalgia). Nausea/vomiting, abdominal pain and fatigue/asthenia were more common in patients aged ≥70 years. Most AEs developed early, within the first 1–2 months of treatment, and resolved within 1–2 weeks. In addition, survival outcomes were better in patients experiencing arthralgia/myalgia or dermatological toxicities. ConclusionThis analysis indicated that, except for rare cases of nephrotoxicity, encorafenib+cetuximab is well tolerated in most patients, with most AEIs being mild-to-moderate in severity, occurring early and resolving rapidly. Clinical Trial Registrationthe BEACON study (ClinicalTrials.gov, NCT02928224; EudraCT, 2015-005805-35)

Effectiveness of first and second-line empirical treatment in Italy: Results of the European registry on Helicobacter pylori management.

The optimal management of naïve and not naïve Helicobacter pylori patients remains unclear. Therefore, it is essential to evaluate whether the actual clinical practice mirrors the indications suggested by the guidelines. This study aimed to assess the effectiveness and the safety of the empirical first- and second-line treatments prescribed to patients enroled at Italian centres participating in the European Registry on H. pylori Management (Hp-EuReg). The Hp-EuReg is an international multicentre prospective non-interventional registry starting in 2013 aiming to evaluate the management of H. pylori infection by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables assessed included demographics, previous eradication attempts, treatment regimen, effectiveness, and tolerance. Overall, 3723 patients from 2013 to February 2021 were included: 2996 and 727 received an empirical first- and second-line treatment, respectively. According to the modified ITT analysis, among the first-line regimens, only the bismuth quadruple therapy with three-in-one-single capsule (BQT-TSC), the concomitant, and the sequential treatment - all lasting 10 days - achieved an eradication rate >90%. Among the second-line regimens, only the 10-day BQT-TSC reported an effectiveness >90%. High-dose PPI twice daily also significantly increased the effectiveness of some therapies. The BQT-TSC was the regimen with the highest incidence of adverse events. Only quadruple therapies lasting at least 10days achieved over 90% eradication rates among the empirical first- and second-line regimens. It remains unclear whether high-dose PPI twice daily can improve the efficacy of quadruple treatment.

1795. Evaluation of Appropriate Daptomycin Usage in an Academic Medical Center

Abstract Background The usage of daptomycin at our institution has steadily increased, with a threefold increase from Jan 2020 to Jan 2022 according to Days of Therapy Data. The increased usage prompted this study to determine whether daptomycin use at our institution is appropriately indicated and supervised by the infection disease service. Methods We conducted a retrospective descriptive study on 74 patients who were selected randomly from a total of 234 pts who received daptomycin at our facility in Northwest Louisiana over the past two years. We studied the patient's age and gender, type of infection, indications, empiric versus targeted therapy, culture results, infectious disease consultation, and reason for early discontinuation. Results Seventy-four pts were included in the analysis. The median age was 53.50 (22-90 yrs), and 47 pts (63.5%) were male. The most common infections were bone and joint (37, 50.7%), followed by bacteremia (22, 30.1%), followed by infective endocarditis (4, 5.5%). The infectious disease service was consulted before administration of daptomycin in 87.3% (62 patients). In 70.3% (52 patients), daptomycin was used as targeted therapy. MRSA was the most common bacteria for which daptomycin was used (29, 42.6%), followed by Enterococcus faecalis (10, 14.7%) and Coagulase-negative staphylococcus (8, 11.8%). Fifty-five pts (74.3%) received vancomycin before switching to daptomycin. The most common indications was MRSA with vancomycin MIC ≥ 2 mcg/ml (25, 33.8%), followed by as an alternative to vancomycin in acute renal failure (14, 18.9%), followed by clinical or/and microbiological failure on the previous antibiotic regimen (10, 13.5%). Thirty-six pts (48.6%) completed their course, 20 (27%) pts had early discontinuation, 11 pts (14.9%) were lost to follow-up, 4 pts (5.4%) were still on daptomycin at the time of data collection, and 3 pts (4.1%) died during hospitalization. The most common cause of early discontinuation was the culture growing pathogen necessitating discontinuation of daptomycin (7 patients, 35%), followed by insurance issues that account for 15%. Conclusion Most daptomycin usage in our institution was wisely indicated under the supervision of the infectious disease service and was primarily used as targeted therapy. Disclosures All Authors: No reported disclosures.

Efficacy and Safety of Tofacitinib in Rheumatoid Arthritis (RA): A Retrospective Study From Two Centers in Jeddah, Saudi Arabia.

Tofacitinib is the first Janus kinase (JAK) inhibitor approved for treating rheumatoid arthritis (RA). Several clinical trials have evaluated the safety and effectiveness of tofacitinib in adult patients with moderately to severely active RA. Real-world studies provide invaluable insights into routine clinical practice. We aim to assess the clinical efficacy and safety of RA patients. Over a period of two years, we included 50 consecutive RA patients who were treated with tofacitinib. Clinical disease activity, assessed by disease activity score (DAS) 28 - erythrocyte sedimentation rate (ESR), as well as adverse events (AEs) were evaluated. A total of 50 patients (84% female) were enrolled in the study. The mean age at initiation of tofacitinib was 48.54 ± 15.97 years. The mean time of treatment with tofacitinib was 18.06 ± 2.04 months. Patients were treated with tofacitinib 5 mg BID with 32% receiving tofacitinib as monotherapy. A total of 74% of the patients had been prescribed at least one biological treatment. The treatment target was achieved in 42 patients (82%). Baseline characteristics and previous treatment regimens did not predict clinical response to tofacitinib. Fifteen patients discontinued the treatment: seven due to ineffectiveness, four due to pregnancy, and five due to adverse events. The most common infectious adverse event was herpes zoster (4%) while the most common observed laboratory abnormalities were elevation in low density lipoprotein (LDL) and high density lipoprotein (HDL) in 6% and 8% of the patients, respectively. Our results indicate that tofacitinib is effectivein real-world settingseven as monotherapy. The treatment target was attained by 82% of the patients on tofacitinib. The safety profile of tofacitinib was generally consistent with previous studies.

Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus-Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma.

Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18-associated HNSCC. In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS). Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7-47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. <25%). DCR-16 was 44.8% (95% CI, 26.5-64.3). Median PFS was 3.5 months (95% CI, 1.9-9.0); median OS was 29.2 months (15.2-not calculable). Twenty-eight (80.0%) patients had treatment-related adverse events [grade 3: 5 (14.3%); no grade 4/5], resulting in discontinuation in 2 (5.7%) patients. HPV-16/18-specific T cells increased on treatment; 4 of 8 evaluable patients had a >2-fold increase in tumor-infiltrating CD8+ T cells. MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.

A multi-center effectiveness comparison study of fruquintinib with constructed external control cohort of other targeted kinase inhibitors using real-world data in third-line treatment of metastatic colorectal cancer.

The objective of this study was to assess the comparative efficacy in third-line setting for metastatic CRC (mCRC) patients using matched population of FRESCO trial with fruquintinib and real-world data with other TKIs. The arm of fruquintinib from the FRESCO phase III trial (NCT02314819) included the data of patients with metastatic CRC that progressed after at least two lines of chemotherapy and received fruquintinib treatment. An external control arm was constructed using real-world data (RWD) of patients who received other TKIs based on key eligibility criteria of FRESCO. The baseline characteristics of two arms was balanced by propensity score matching (PSM). The Kaplan-Meier method and Cox proportional hazard model was used to evaluate progression free survival (PFS) and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), respectively. Overall, 128 patients were successfully matched by PSM in each, fruquintinib and other TKIs group. The patients in fruquintinib group showed significant increase in median PFS than other TKIs (3.71 vs. 2.49 months, HR = 0.67, 95%CI, 0.48-0.94, p = 0.019). In the subgroup analysis, fruquintinib showed a significant benefit in PFS compared with other TKIs among patients undergoing two or three previous chemotherapy regimens (HR 0.58, 95%CI 0.40-0.84; p=0.004), with rectum as primary disease site (HR 0.52, 95%CI 0.31-0.87; p=0.013), with left sided primary tumor location (HR 0.62, 95%CI 0.42-0.90; p=0.011), with multiple metastasis sites (HR 0.68, 95%CI 0.48-0.97; p=0.034) and with lung metastasis (HR 0.65, 95%CI 0.43-0.98; p=0.042). With the approach of establishing the external control arm from RWD, this study has demonstrated that treatment with fruquintinib significantly prolonged PFS as compared to other TKIs in patients as third-line mCRC treatment.

Efficacy and safety of anamorelin in patients with cancer cachexia: Post-hoc subgroup analyses of a placebo-controlled study.

Cachexia, a disorder associated with anorexia, inflammation, and muscle wasting, is frequent in cancer patients. We performed post-hoc analyses of the ONO-7643-04 study to investigate the efficacy and safety of anamorelin in subgroups of Japanese patients with non-small cell lung cancer (NSCLC). The patients were divided into subgroups by baseline characteristics, including sex, age, body mass index, prior weight loss, performance status (PS), concomitant anticancer therapy, and number of previous chemotherapy regimens. The changes from baseline through to 12 weeks for lean body mass (LBM), body weight, and appetite were calculated. Appetite was evaluated using the quality of life questionnaire for cancer patients treated with anticancer drugs (QOL-ACD) item 8 score. Responder rates were defined as the maintenance/improvement of LBM (≥0kg), body weight (≥0kg), or QOL-ACD item 8 score (≥0) from baseline to all evaluation time points. Safety was evaluated in patients subgrouped by age and PS. Anamorelin resulted in greater improvements versus placebo in LBM, body weight, and appetite in most subgroups. Anamorelin was also associated with greater LBM, body weight, and appetite responder rates than placebo in nearly all subgroups. Among anamorelin-treated patients, adverse drug reactions (ADRs) tended to be more frequent with increasing age (<65 years, 19.2%; ≥65 to <75 years, 45.9%; ≥75 years, 60.0%) and PS score (PS 0-1, 38.4%; PS 2, 60.0%). The frequency of serious ADRs was 2.7% and 0% in the PS 0-1 and PS 2 subgroups, respectively. This study of NSCLC patients with cancer cachexia revealed consistent improvements in LBM, body weight, and appetite across most subgroups of anamorelin-treated patients. This study also demonstrated the tolerability of anamorelin regardless of age and PS, with a low incidence of serious ADRs in each subgroup.

IgD Multiple Myeloma, Does It Still Have a Poor Prognosis?

IgD Multiple myeloma is considered unusual myeloma, with just 2% of cases of MM being diagnosed as IgD subtype. The infrequency of its presentation and the poor prognosis make the disease challenging to treat, with many patients being selected for clinical trials. A 63-year-old female presented to the ER after falling on ice. After undergoing a CT Head, multiple lytic lesions in the occipital region were found, confirmed by MRI. 2 months later, a bone marrow biopsy found 90% of marrow replaced by CD138 plasma cells, positive for kappa & negative for lambda, consistent with myeloma. On evaluation, she was found to have pan-hypo-gammglobulinemia. However, the skeletal survey did not find any other lytic lesions. Seeing this, IgD levels were measured and found to be >100 times over the upper normal limit with normal beta2-microglobulin levels, confirming monoclonal gammopathy. A FISH study found the patient positive for t(11;14)/CCND1IGH translocation (85% of cells) and negative for TP53. Palliative radiotherapy for the skull base was performed before the patient started chemotherapy. The patient was deemed a suitable candidate, selected for a clinical trial, and placed on RVd [revlimid + velcade + dexamethasone] with delayed bone marrow transplant. As the patient developed a rash and neuropathy from velcade [bortezomib], it was paused and restarted after three months. The patient was doing well on this chemotherapy regimen for two years and was placed on lenalidomide-based maintenance therapy. Two years later, her disease started progressing with an increased frequency of bone pains and opioid dosing. At this juncture, it was decided to change course and start her on pomalidomide/dexamethasone. This did not help the patient, and the neurological side effects of dexamethasone made us change course and initiate a daratumumab, bortezomib, cyclophosphamide and dexamethasone. This proved unfruitful, too, as the patient developed adverse effects of polyneuropathy, pancytopenia requiring transfusion, and worsening GERD. Seeing the disease relapse and intolerance to the previous regimen, we decided to initiate a once-per-week regimen of selinexor, bortezomib, and dexamethasone. The patient has improved on this regimen and is back to her baseline for physical activity, mental status and pain, and an improved appetite. In this case, we wanted to highlight how incidental findings on a CT lead us to diagnose a rare type of multiple myeloma and how, in the era of novel agents, the survival of patients can be prolonged significantly. Considering the rarity of this subtype, international collaborative studies are suggested to further elucidate the underlying mechanisms for developing potent therapeutic approaches. Most of the data reported on how IgD multiple myeloma progresses was written before the arrival of novel agents. More evaluation of survival times and progression of the disease needs to be done as it's possible that IgD MM is not as poor a prognosis as it once was.

SC-gtCAR19, a Non-Viral Genome Targeting Anti-CD19 CAR-T Candidate in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia: Updated Results from Long-Term Follow-up

Introduction It has been made great commercial success in hematological malignancies by chimeric antigen receptor (CAR) T cell therapy. However, high rate of adverse events (AEs) still remains an issue. Non-viral Genome Targeting CAR (gtCAR) delivery technology, which uses CRISPR-Cas9 to insert CAR DNA to TRAC locus specifically in human T cells, produces moderate CAR-T cells compared with conventional ones. Earlier results of SC-gtCAR19, an anti-CD19 gtCAR-T candidate from an investigator initiated Phase I clinical trial (ChiCTR2000031942) demonstrated a favorable benefit-risk profile in relapsed/refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL) patients. Reported here are updated long-term follow-up results. Objective The primary objective is to assess safety. Secondary objective is to evaluate efficacy. Level of CAR-T cell in blood was explored. Method This is a single center, open-label and single-arm trial. Patients or allogeneic donors underwent leukapheresis and their CD3+ T cells were selected and modified by non-viral vector to produce SC-gtCAR19. A standard lymphodepletion chemotherapy was performed. The median dose was 3.89×106CAR+ cells/kg (0.58-8.31×106/kg). AEs were graded according to CTCAE v5.0. Cytokine Release Syndrome (CRS) and neurological events (NEs) were graded by ASTCT consensus grading. Relapse defined as bone marrow (BM) blast or B-ALL related mutation gene positive from nonexistence regardless of specific value, and extramedullary disease (EMD) occurrence. Result As of May 1st 2022, twenty-two r/r B-ALL patients received SC-gtCAR19 (Table 1). The median age was 29 (13-61), and the median number of previous regimen was 5 (2-16). The median baseline BM blast after preconditioning was 44.1% (0.3-99%), particularly 73% of patents with high disease burden (>25% leukemic blast). Five patients (23%) once had stem cell transplantation (SCT), and 14 (64%) have B-ALL related chromosomal and molecular abnormalities. One patient has EMD. No patient has been treated by any other CD19 related therapy before enrollment. The most common AEs of any grade were anaemia (100%), pyrexia (91%), neutrophil count decreased (91%), and white blood cell count decreased (86%) (Table 2). CRS occurred in 20 patients (91%), and 4 of them (18%) with grade 3 CRS. The median time to CRS onset was 7 days (IQR 7-14), and the median duration of any grade CRS was 3 days (IQR 2-5). Three patents developed NEs, one was grade 2 and 2 were grade 3 (temporary seizure, related to infection and patient's cerebral infarction before enrollment). No fatal or life-threatening events happened. No Tocilizumab administered, four patients used vasopressors and 2 steroids for treatment of CRS. All patients were eligible for efficacy analysis. At Day 28, the overall response rate was 100%, with 9 (41%) patients achieving complete remission (CR), ten (45%) achieving complete remission with incomplete haematological recovery (CRi), and 3 (14%) with blast-free hypoplastic. Among them, twenty patients (91%) achieved minimum residual disease (MRD) negative CR, and those 2 patients with MRD positive CR were assessed undetectable BM MRD in Day 90. Patient with EMD, the nodal lesions in her breast disappeared at Day 60. At a median follow-up of 19.9 months (4.5-26.6), nineteen patients relapsed, within which 7 (36.8%) antigen escape relapse. The median duration of remission for 19 patients achieving CR/CRi was 8 months (2.5-NE). All patients received a consolidation treatment by Lenalidomide 3 months after infusion on condition of CR status until disease progression/death, and all of them did not receive SCT afterwards before relapse. As of the data cutoff, two patients (9%) had ongoing CR with median follow-up of 22.4 months. The median relapse-free survival for 19 patients was 8.9 months (2.9-NE) (Figure 1). The median OS was 24.2 months (3.7-NE) (Figure 2). CAR T cell level measured by cell copies percentage per peripheral blood mononuclear cells peaked at median 12 days (IQR 10-13) (Figure 3). The median peak percentage of copies was 53% (IQR 26.5-72.1%). Conclusion This study is the first clinical trial applied a gtCAR-T candidate for r/r B-ALL treatment. SC-gtCAR19 has a better risk-tolerance. Despite TCR gene knocked-out, gtCAR-T cell proliferation and its function both short and long term may not be influenced. We illustrate that this novel approach is feasible in terms of manufacture and clinical application. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Conversion to Belatacept in kidney transplant recipients with chronic antibody-mediated rejection (CAMR)

BackgroundThe costimulatory inhibitor Belatacept (Bela) has been shown to be an effective alternative in several clinical situations, including chronic antibody-mediated rejection, calcineurin toxicity, and de novo alloantibody formation. To further explore the usefulness of Belatacept under various clinical scenarios, we performed a retrospective analysis of a prospective database of all recipients who had a BPAR diagnosis of CAMR and were converted to a Belatacept maintenance immunosuppression regimen after kidney transplantation. Material and methodWe conducted a retrospective analysis of a prospectively collected database of all kidney transplants adult patients at SUNY Upstate Medical Hospital from 1 January 2013 to 31 December 2021. Our inclusion criteria were the patients who have been diagnosed with CAMR according to their renal biopsy based on the 2013 Banff criteria. The primary objective was to compare the kidney viability and function using GFR between the two interest groups and finally compare the outcomes. ResultsA total of 48 patients met our inclusion criteria based on the kidney biopsy result, which showed chronic antibody-mediated graft rejection (CAMR). Nineteen patients (39.6%) were converted to the Belatacept, and we continued the previous immunosuppression regimen in 29 patients (60.4%). The mean time from the transplant date to the diagnosis of CAMR was 1385 days in the Belatacept group and 914 days for the non-Belatacept group (P = 0.15). The mean GFR comparison at each time point between the groups did not show a significant difference, and Belatacept did not show superiority compared to the standard immunosuppression regimen in terms of kidney function preservation. 1 (5.2%) patient from the Belatacept group and 1 (3.4%) patient from the non-Belatacept group had a biopsy-proven acute rejection (BPAR) after CAMR confirmation, and it was comparable (P = 0.76). De novo synthesis of the DSA rate was 12.5% in the Belatacept group and 15% In the non-Belatacept group, which was comparable. (P = 0.90). The patient survival rate was 100% in both groups. ConclusionsWe conclude that compared to the standard Tacrolimus/MMF/Prednisone regimen, Belatacept did not significantly benefit in preserving the GFR in long-term follow-ups and stabilizing the DSA production, which is one of the main factors resulting in chronic graft failure.

Efficacy and safety of daratumumab in patients with relapsed/refractory multiple myeloma

Objective: To investigate the efficacy and safety of daratumumab in relapsed/refractory multiple myeloma (RRMM) patients. Methods: Fifty-two RRMM patients treated with daratumumab from September 2019 to November 2021 in West China Hospital were retrospectively enrolled, including 31 males and 21 females. The mean age of these patients at the first diagnosis of multiple myeloma was (58±10) years. According to the dosage of daratumumab, patients were divided into low dosage group (n=10) and high dosage group (n=42). Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse event rates were investigated. Univariate and multivariate analysis of potential factors were conducted. Results: Of the 52 patients, 8 received daratumumab monotherapy, 27 received daratumumab plus immuno-modulatory drug (IMiD) treatment, 4 received daratumumab plus proteosome inhibitor (PI) treatment, and 11 received daratumumab plus dexamethasone treatment. The diagnosis age of high dosage group patients was (57±9) years, which was significantly younger than that of low dosage group [(66±10) years] (P=0.009). The baseline creatinine level of high dosage group patients [M (Q1, Q3)] was 91 (68, 196) μmol/L, which was significantly higher than that of low dosage group [66 (51, 76) μmol/L] (P=0.021). There was no significant difference in other baseline clinical characteristics, previous treatment regimens, previous lines of treatment, and regimen and cycles of daratumumab between the high dosage group and low dosage group (all P>0.05). The ORR for the 52 patients was 71.2% (37/52). The ORR for daratumumab plus IMiD group was 81.5% (22/27), which was significantly higher than that in monotherapy or dexamethasone group [ORR: 52.6% (10/19), P=0.036). With a median follow-up [M (Q1, Q3)] of 7 (5, 26) months, the median PFS for overall cohort was 17 (95%CI: 9.6-24.4) months. The median PFS for daratumumab plus IMiD group was 26 (95%CI: 6.0-46.0) months, which was significantly better than that in monotherapy or dexamethasone group [12 (95%CI: 3.5-20.5) months] (HR=0.231, 95%CI: 0.075-0.715, P=0.011). Higher diagnosis age was the risk factor of progression (HR=1.085, 95%CI: 1.016-1.158, P=0.014), while more cycles of daratumumab treatment was the protective factor of progression (HR=0.669, 95%CI: 0.495-0.904, P=0.009). There was no significant influence of daratumumab dosage on progression (high dosage vs low dosage, HR=1.016, 95%CI: 0.221-4.668, P=0.984). The median OS for overall cohort was 26 (95%CI: 13.1-38.9) months. Higher serum calcium was the independent risk factor of death (HR=12.190, 95%CI: 1.170-127.048, P=0.037). There was no significant influence of daratumumab dosage on death (high dosage vs low dosage, HR=0.818, 95%CI: 0.171-3.917, P=0.802). Adverse events included infections (43.2%, 16/37), infusion-associated reactions (29.7%, 11/37), and thrombocytopenia (27.0%, 10/37). Conclusions: Daratumumab is effective to treat RRMM. The dosage of daratumumab has no significant influence on prognosis when used in combined treatment. The incidence of adverse events is relatively low, with a favorable safety profile.

Prevalence of neuropsychiatric adverse events and associated factors among adult patients on dolutegravir attending Mulago ISS clinic.

Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor that is recommended by the World Health Organization as the preferred first-line and second-line antiretroviral therapy (ART) in patients with HIV. In 2018, Uganda started using DTG-based regimens as the preferred first-line ART. However, concerns regarding the potential neurotoxicity of DTG have been increasing. Data on the occurrence of neuropsychiatric adverse events (NPAEs) and the associated factors among adult patients who are initiated on or switched to DTG-based first-line or second-line ART in Uganda are limited. This study aimed to determine the prevalence of NPAEs among adult patients on DTG and the factors associated with their occurrence. We conducted a cross-sectional study using questionnaires administered by a trained research assistant between 15 November 2021 and 15 December 2021. The study included patients aged ≥18 years with HIV who were either initiated on or switched to a DTG-based ART regimen between 1 January 2018 and 31 October 2021. Informed consent and data were collected from 892 participants attending Mulago ISS clinic, including data on age, sex, marital status, disclosure status, current regimen, duration on ART, concurrent illness, concurrent medications, year of switch to DTG, duration on DTG, whether the onset of NPAEs was immediate or delayed, history of alcohol use or smoking, level of education, report of NPAEs while on DTG, and history of NPAEs while on previous regimen. Data were entered into Epidata version 4.6.0.2 then exported to Stata version 14 for analysis. Of the 892 adults on DTG attending Mulago ISS clinic, 41.7% (95% confidence interval [CI] 38.5%-44.9%) experienced at least one NPAE. DTG duration in years (adjusted prevalence [aPR]=1.21, p=0.024), disclosure status (aPR=1.40, p=0.042), concurrent medications (aPR=1.31, p=0.026), year of switch to DTG, and concurrent illness were associated with an increased occurrence of NPAEs. The prevalence of NPAEs was higher than that reported by any clinical trial. About 9.1% of participants had experienced severe to life-threatening NPAEs that required intervention from a healthcare professional to improve tolerability. The high prevalence requires that clinicians screen for NPAEs at very visit and reassure patients to maximize the benefits of long-term ART.

Improvement of Body Weight and Nutritional Status in Gastric Cancer Patients Enhances the Benefit of Nivolumab Therapy.

Nivolumab improves overall survival (OS) in patients with advanced gastric cancer (AGC) refractory to at least two previous chemotherapy regimens. We investigated whether changes in body weight and nutrition from first-line chemotherapy to nivolumab affected its efficacy. The correlation between weight change and nutritional status up to the start of nivolumab treatment and OS and progression-free survival (PFS) after starting nivolumab treatment was determined. Nutritional status was examined using the C-reactive protein/albumin ratio (CAR). A loss in body weight (LBW) from the onset of the first treatment of <4.5% led to OS prolongation and improved PFS outcomes. The median OS values in the LBW < 4.5% and ≥4.5% groups were 11.4 and 3.6 months, respectively. Similarly, changes in CAR from first-line chemotherapy (ΔCAR) affected OS; the ΔCAR < 0.01 group had a better prognosis than the ΔCAR ≥ 0.01 group. The median OS values in the ΔCAR < 0.01 and ≥0.01 groups were 9.4 and 4.5 months, respectively. The median OS in the group with LBW < 4.5% and ΔCAR < 0.01 was 12.9 months. LBW and deterioration of nutritional status following first-line chemotherapy are poor prognostic factors in AGC patients who received nivolumab as third- or later-line therapy. Early intervention to maintain body weight and nutritional status may improve the efficacy of immune checkpoint inhibitors.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.

Towards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.