Months Of Combination Therapy Research Articles

Enzyme replacement therapy and immunotherapy lead to significant functional improvement in two children with Pompe disease: a case report

BackgroundPompe disease, a rare autosomal recessive disorder caused by acid alpha-glucosidase deficiency, results in progressive glycogen accumulation and multisystem dysfunction. Enzyme replacement therapy with recombinant human acid alpha-glucosidase is the standard of care; however, some patients develop anti-recombinant human acid alpha-glucosidase antibodies, leading to reduced efficacy. This case report presents two infants with early-onset Pompe disease who developed IgG antibodies to enzyme replacement therapy and were subsequently treated with methotrexate, highlighting the importance of monitoring antibody development and exploring alternative therapeutic approaches.Case presentationPatient 1, a 10-month-old female from Bogota, Colombia, presented with generalized hypotonia, macroglossia, hyporeflexia, and mild left ventricular hypertrophy. Diagnostic tests confirmed early-onset Pompe disease, and enzyme replacement therapy was started at 12 months. Due to a lack of improvement and high anti-recombinant human acid alpha-glucosidase IgG antibody titers (1:1800), methotrexate was started at 18 months. After 8 months of combined therapy, antibody titers were negative and significant improvement in motor function was observed using the Gross Motor Function Measure 88. Patient 2, a 7-year-old female from Bogota, Colombia, was diagnosed with early-onset Pompe disease at 12 months and initiated enzyme replacement therapy. At 5 years of age, she experienced frequent falls and grip strength alterations. Functional tests revealed motor development delay, generalized hypotonia, and positive anti-recombinant human acid alpha-glucosidase IgG antibody titers (6400). Methotrexate was initiated, leading to a reduction in falls and antibody titers (3200) after 6 months, with no adverse events or complications. Motor function improvement was assessed using the Motor Function Measurement 32.ConclusionsThe presented cases highlight the importance of monitoring patients for anti-recombinant human acid alpha-glucosidase antibody development during enzyme replacement therapy and the potential benefit of methotrexate as an immunomodulatory agent in early-onset Pompe disease. Early diagnosis and timely initiation of enzyme replacement therapy, combined with prophylactic immune tolerance induction, may improve clinical outcomes and reduce the development of anti-recombinant human acid alpha-glucosidase antibodies. The cases also highlight the importance of objective motor function assessment tools, such as Gross Motor Function Measure 88 and Motor Function Measurement 32, in assessing treatment response. Further research is needed to optimize treatment regimens, monitor long-term effects, and address the current limitations of enzyme replacement therapy in Pompe disease.

A rare family outbreak of Mycobacterium abscessus infection in immunocompetent fraternal triplets

BackgroundMycobacterium abscessus (M. abscessus) infection is rare in children who were previously healthy, particularly in infants. We present the first report of a family outbreak of M. abscessus infection among immunocompetent infant triplets. MethodsWe reviewed triplets’ demographic data, laboratory tests and imaging examinations to describe their clinical features. We performed whole-exome sequencing to rule out primary immunodeficiency disorders. We used DNA sequencing for M. abscessus subspecies identification. ResultsThe fraternal triplets (triples A, B and C) presented with a 10-day history of cough. Triple A also experienced a brief episode of fever, and triple B had tachypnea. Chest CT scans showed pulmonary masses and nodules in triples A and C, and cavities in triple B. Cultures of sputum and bronchoalveolar lavage fluid from all triplets yielded M. abscessus. Further subspecies identification showed that isolates from triples A and C were M. abscessus subsp. massiliense, and isolates from triple B were M. abscessus subsp. abscessus (MAA). After eight months of combination therapy, the pulmonary lesions of the triplets improved significantly. ConclusionOur study confirms that M. abscessus pulmonary disease can occur in immunocompetent infants. We hypothesize that the simultaneous infection of the triplets may be associated with their prematurity and extensive environmental exposure. This study highlights the importance to include M. abscessus infection in the differential diagnosis of pulmonary masses and/or cavities, regardless of the age of onset or the presence of underlying pathology or susceptible genes.

INFLUENCE OF STATINS ON ARTERIAL STIFFNESS AND BLOOD PRESSURE CONTROL IN PATIENTS WITH SEVERE ARTERIAL HYPERTENSION

Objective: In some studies, there was well established a statin influence on arterial stiffness. It was suggested statins could decrease the blood pressure too. Pulse wave velocity (PWV), a gold standard for arterial stiffness measurement, depends on blood pressure (BP). The aim of study was to evaluate the influence of statins on PWV changes in dependency on normalization of the 24-h BP. Design and method: In study, there were included 46 patients (mean age 55.6 ±1.07, f/male 47.8/52.2%) with systolic (SBP)/diastolic (DBP) BP >/=180/110 mmHg, who were treated in specialized unit. Baseline and at the 6th month of combination therapy (mean medicines - 3.8±1.2), we provided office/ambulatory BP and PWV measurements. Results: At 6th month, only 39.1% had 24-h BP <130/80. PWV changes under treatment are present in tab. In statin treatment group we noted significant PWV lowering in spite of BP control. In patients without statins, PWV decreased significantly only in subgroup with achieved the target 24-h BP. In statin group 66.7% achieved target 24-h BP compared to 33.3% in statin (-) group (p=0.048). Conclusions: The statin therapy is able to improve the arterial stiffness (independently to BP control) and helps to achieve the target BP.

Observing the clinical efficacy of combined serum microneedle therapy for moderate to severe androgenetic alopecia in scalp repair.

In this study, the safety and efficacy of scalp repair serum microneedles combined with oral drug administration and topical medication were investigated for the treatment of moderate to severe androgenetic alopecia. Twenty patients, consisting of 4 males and 16 females, who sought treatment for moderate to severe androgenetic alopecia at our hair medicine research center alopecia specialty clinic between August and December 2022 were randomly selected for the study. Male patients underwent oral administration of finasteride topical application of 5% minoxidil, and biweekly scalp repair serum microneedle therapy. Female patients were administered spironolactone or Diane-35 orally and applied 2% minoxidil topically, paired with biweekly scalp repair serum microneedle therapy sessions. After seven treatments, the scalp repair serum microneedle was discontinued, but oral administration and topical applications were continued, followed by a 1-month follow-up. Using a hair dermoscopy, hair follicles in a fixed region on the top of the head were manually counted per unit area to evaluate the hair restoration status of the patients quantitatively. All 20 patients completed 3 months of combined therapy and a 1-month follow-up. On average, the patients experienced an increase of 42.6 hairs, with an efficiency rate of 100%. Significant differences were observed in hair count between any two of the first seven treatments (p<0.001). A significant negative correlation was discovered between the initial pre-treatment hair count and the total improvement of hair (p<0.001), indicating that the greater the degree of hair loss before treatment, the more pronounced the improvement. Scalp repair serum microneedle combined therapy in moderate to severe androgenetic alopecia significantly reduces the number of microneedle treatments required, enhances treatment efficacy, and improves therapeutic outcomes.

Effectiveness of rifaximin and probiotics for the correction of intestinal permeability in patients with metabolic-associated fatty liver disease in combination with type 2 diabetes mellitus.

Aim: To investigate the effectiveness of rifaximin and probiotics for the correction of intestinal permeability in patients with metabolic-associated fatty liver disease (MAFLD) in combination with type 2 diabetes mellitus. Materials and Methods: The prospective interventional randomized investigation included 68 patients with MAFLD in combination with type 2 diabetes, who were examined and divided into the 2 groups of treatment. Results: The serum levels of interleukin (IL) - 6, IL-10 and zonulin, indicators of liver functional activity, liver attenuation coefficient between treatment group vs. control group after 2 weeks, 1 month, 3 and 6 months of therapy were significant differed. The serum levels of IL-6 and zonulin significantly decreasing and increasing of IL-10 in the treatment group after 2 weeks, 1, 3 and 6 months of combined therapy. When comparing of stool short-chain fatty acids concentration between treatment group vs. control group after 2 weeks, 1 month, 3 and 6 months of therapy the levels of acetic, butyric and propionic acids significantly differences and increase in their levels were established. Conclusions: The results of the study in dynamics during 6 months show that the additional appointment of rifaximin, multispecies probiotic and prebiotic to metformin in patients with MAFLD and type 2 diabetes led to the elimination of subclinical inflammation, modulation of the permeability of the intestinal barrier and lowering increased intestinal permeability, as well as to the lower serum activity of liver aminotransferases and decrease the stage of steatosis.

Anti-GPIb/IX Autoantibodies Are Associated with Poor Response to Dexamethasone Combined with Rituximab Therapy in Primary Immune Thrombocytopenia Patients

This retrospective study aimed to evaluate whether anti-glycoproteins (GPs) autoantibodies can be used as predictors of response to high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) patients. According to the screening criteria (Figure. 1), 126 ITP patients, including 85 (67.5 %) women and 41 (32.5 %) men, were included in the analyses, with a median age was 32 (10 - 80) years, the median duration of disease was 18 (0.1-228.0) months, and the median platelet count at baseline was 6.0 (0-28.0) × 10 9/L. As shown in Table 1, 56.4% (71/126) of patients responded to DXM-RTX at four weeks, including 43 CR and 28 partial responses. The median time to response (TTR) of 71 responded patients was seven days (range: 4-28 days). The OR rate of ITP patients with anti-GPIb/IX positivity was 47.6% (40/84), while that of anti-GPIb/IX autoantibody-negativity was 73.8% (31/42) (χ 2 = 7.808, P = 0.005). In line with the OR rate, a significant difference was found in the CR rate between ITP patients with anti-GPIb/IX positivity and anti-GPIb/IX autoantibody-negativity (26.2% vs. 50.0%, χ 2 = 7.061, P = 0.008). At six months of DXM-RTX therapy, 54.0% (68/126) of patients responded to DXM-RTX, with 39 (31.0%) of CR. The CR and OR rates of anti-GPIb/IX autoantibody-positive patients were also significantly lower than those of negative patients (CR: 45.2% vs. 71.4%, χ 2 = 7.731, P = 0.005; OR: 25.0% vs. 42.9%, χ 2 = 4.178, P = 0.041). No significant difference ( P &amp;gt; 0.05) was found in OR and CR rates between anti-GPIIb/IIIa autoantibody positive and negative patients at four weeks and six months of DXM-RTX therapy. At four weeks of DXM-RTX therapy, a significant difference in OR rate was found among the patients with anti-GPIb/IX single-positivity (37.5%), double-positivity (51.7%), double-negativity (68.4%), and anti-GPIIb/IIIa single-positivity (78.3%) (χ 2 = 9.617, P = 0.022) (Table 2). The further comparison revealed a higher resistance to DXM-RTX in patients with anti-GPIb/IX single-positivity than patients with anti-GPIIb/IIIa single-positivity (OR: 37.5% vs. 78.3%; P &amp;lt; 0.05). A similar trend was also found in the six-month OR rate (29.2% vs. 78.3%, P &amp;lt; 0.05). An analysis of the CR rate at four weeks of therapy showed a significant difference among the four groups (χ 2 = 8.523, P = 0.036) but no significant difference after Bonferroni's correction ( P &amp;gt; 0.05). No significant difference ( P = 0.119) was found in the CR rate among the four groups at six months of combined therapy. In addition, the NR rate of patients with anti-GPIb/IX single-positivity also increased significantly in comparison with the patients with anti-GPIIb/IIIa single-positivity at four weeks (62.5% vs.21.7%, P &amp;lt; 0.05) and six months (70.8% vs.21.7%, P &amp;lt; 0.05) of combined therapy. Multivariate logistic regression analyses revealed that age, sex, duration of disease, liver function, and baseline platelet count were not associated with patient response to DXM-RTX at 4 weeks and 6 months (Table 3). Anti-GPIb/IX autoantibodies and megakaryocytes of DXM-RTX therapy at both 4 weeks and 6 months were associated with the OR rate of patients, with an odds ratio of 0.194 ( P = 0.003, 95% CI: 0.065-0.575) at 4 weeks and 0.189 ( P = 0.003, 95% CI: 0.064-0.563) at 6 months by comparing patients with anti-GPIb/IX autoantibodies to those without anti-GPIb/IX autoantibodies. The factorial design analyses revealed no interaction effect between autoantibodies and showed anti-GPIb/IX autoantibodies at 4 weeks represented the only significant factor affecting OR rate with DXM-RTX therapy (F = 9.128, P = 0.003, Table 4). Therefore, platelet anti-GPIb/IX autoantibodies can predict poor response to DXM-RTX in ITP patients.

Tazemetostat in Combination with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Updated Phase 1b Results of Symphony-1 with 22.5 Months Follow-up

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies, or patients with R/R FL who have no satisfactory alternative treatment options. We previously reported the efficacy and safety of TAZ in combination with lenalidomide and rituximab (R 2) in patients with R/R FL from the SYMPHONY-1 study (EZH-302; NCT04224493) after complete enrollment and following the phase 1b safety run-in period. Here, we report the updated efficacy and safety results after a median follow-up of 22.5 months. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R 2. After the initial 12 months of combination therapy, tazemetostat 800 mg BID was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoints of the phase 1b portion were safety and determination of the recommended phase 3 dose (RP3D). Secondary endpoints included pharmacokinetic (PK) parameters. Efficacy analysis was performed on the intent-to-treat (ITT) population, including best overall response, progression-free survival (PFS), and duration of response (DOR) per investigator assessment, according to Lugano 2014 response criteria. Results: As of July 10, 2023, 44 patients were enrolled and receiving TAZ + R 2 (400 [n=6], 600 [n=19], or 800 mg [n=19]). Median age was 67 years, 31.8% of patients had received &amp;gt;1 prior therapy, and patients had a median of 1 prior line of therapy (range, 1-4). Overall, 81.8% (n=36) of patients had wild-type (WT) EZH2 FL, 34.1% (n=15) of patients had rituximab-refractory disease, and 27.3% (n=12) of patients had POD24. Median durations of treatment exposure for TAZ, lenalidomide, and rituximab were 13.3, 10.8, and 4.6 months, respectively. In the 800-mg cohort, the median relative dose intensity was 94.1%, 92.9%, and 100% for TAZ, lenalidomide, and rituximab, respectively. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the data cutoff. The RP3D of TAZ was determined to be 800 mg BID in combination with R 2. The most common grade 3-4 TEAE was neutropenia (40.9%; n=18). The most frequent type of dose modification due to TEAEs for any study treatment was drug interruption (70.5%), followed by dose reduction (38.6%) and treatment discontinuation (20.5%); protocol-mandated dose modifications included simultaneous dose interruption and/or reduction of TAZ and lenalidomide for neutropenia and thrombocytopenia. Of the 44 patients, 42 patients were evaluable for tumor assessment and 2 patients had no postdose tumor assessments. Of 42 patients evaluable for tumor assessment, 23 (54.8%) had a complete response, 17 (40.5%) had a partial response, and 2 (4.8%) had stable disease. The ORR in the ITT population was 90.9% (n=40/44). The ORRs in patients with WT EZH2 and MT EZH2 were 88.9% (n=32/36) and 100% (n=7/7), respectively. The ORR in patients with rituximab-refractory disease was 93.3% (n=14/15) and in patients with POD24 was 91.7% (n=11/12). With a median follow-up of 22.5 months, median PFS and median DOR were not reached. In the ITT population, 18-month PFS and DOR estimates were 79.5% and 81.0%, respectively; in the 800-mg cohort (n=19), 18-month PFS and DOR estimates were 94.4% and 100%, respectively. PFS appeared to be dose dependent, with durable response in the 800-mg cohort. Conclusions: The safety profile of TAZ + R 2 combination therapy was consistent with previous reports, with no new safety signals identified in the phase 1b data of this study. The 12 months of initial combination therapy resulted in long-lasting remission. Dose-dependent response was seen with durable response in patients receiving TAZ 800 mg, regardless of their mutation status. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ 800 mg + R 2 in ≈500 patients with R/R FL who completed ≥1 prior systemic therapy.

Comparison of Efficacy and Safety of Anti-Programmed Cell Death-1 Antibody Plus Lenvatinib and Chemotherapy as First-Line Therapy for Patients with Stage IV Gallbladder Cancer: A Real-World Study in a Chinese Population.

Background: The present study aimed to evaluate and compare the efficacy and safety of anti-programmed cell death protein 1 (anti-PD-1) antibody plus lenvatinib (tyrosine kinase inhibitor) therapy and chemotherapy as the first-line treatment to unresectable stage IV gallbladder cancer (GBC). Methods: We retrospectively analyzed the clinical data of patients with stage IV GBC who received chemotherapy or anti-PD-1 antibody combined with lenvatinib therapy at our hospital from March 2018 to October 2022. Patients with previous antitumor treatment were excluded. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were assessed. Results: A total of 64 patients were enrolled, of which 33 patients received chemotherapy (gemcitabine + cisplatin) in the chemotherapy group, and 31 patients received anti-PD-1antibody (camrelizumab) combined with lenvatinib therapy in the combined therapy group. The median OS was 12.00 months in the combined therapy group and 10.00 months in the chemotherapy group (hazard ratio (HR), 0.57; 95% CI: 0.32-1.03; p < 0.05). The median PFS was 9.00 months in the combined therapy group and 6.00 months in the chemotherapy group (HR, 0.46; 95% CI: 0.25-0.84; p < 0.01). The ORR was 54.84% and 39.39% in the combined therapy and chemotherapy groups, respectively, and the difference was not significant (p = 0.22). The DCR was 80.65% and 72.72% in the combined therapy and chemotherapy groups, respectively (p = 0.46). One patient successfully underwent radical surgery after 8 months of combined therapy and achieved a pathological complete response. Furthermore, no patients experienced AEs of hematologic toxic effects in the combined therapy group compared with the chemotherapy group, demonstrating the advantage of the combined therapy. Conclusions: Anti-PD-1 antibody combined with lenvatinib may be a potentially effective and tolerable first-line treatment for unresectable stage IV GBC.

Combined Prophylaxis of Chronic Migraine with OnabotulinumtoxinA and Anti-CGRP Antibodies

Objective: To evaluate the efficacy of adding large molecule anti-calcitonin gene-related peptide monoclonal antibodies (mAbs) to onabotulinumtoxinA (OBT-A) for chronic migraine prevention. Background: Chronic migraine (CM) is a highly prevalent, debilitating disorder that leads to personal, social, and economic burdens. Both OBT-A and mAbs are proven safe and effective in chronic migraine prevention. The use of combination therapy has not been formally studied but may prove more effective than either monotherapy alone in select patients. Methods: This is a retrospective chart review of patients with chronic migraine, treated with OBT-A, who received additional mAb preventative therapy. The primary endpoint was migraine headache days per month (MHD) after 3 months of combined therapy. Secondary endpoints included total headache days per month, headache intensity, disability level, and use of abortive medications. Results: Of 1503 patients reviewed, 133 met inclusion criteria. At 3 months of combined therapy, mean reduction of MHD from baseline was 6.2 (95% CI 4.91 to 7.49, p &lt; 0.0001). Nearly 2/3rd of patients (60.9%) experienced ≥ 50% MHD reduction. Fewer patients reported high disability level (14.6% [17/126], compared to 29.4%) and high headache intensity (13.0% [16/119], compared to 51.3%) at 3 months (all p &lt; 0.0001). A reduction in abortive medication doses needed and discontinuation of concomitant oral preventative medications was also noted in 15.8% and 6.8% of patients, respectively. Conclusions: Combined therapy with OBT-A and mAbs is well-tolerated, effective in further reducing migraine frequency, and may improve quality of life for patients with CM refractory to monotherapy.

Adverse events during first-line treatments for mCRC: The Toxicity over Time (ToxT) analysis of three randomised trials

BackgroundIn clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs evaluation, taking into account chronic low-grade AEs, single patient’s perspective, and time-related information, such as ToxT analysis, should be considered especially for less intense but potentially long-lasting treatments, such as maintenance strategies in metastatic colorectal cancer (mCRC). Patients and methodsWe applied ToxT (Toxicity over Time) evaluation to a large cohort of mCRC patients enroled in randomised TRIBE, TRIBE2, and VALENTINO studies, in order to longitudinally describe AEs throughout the whole treatment duration and to compare AEs evolution over cycles between induction and maintenance strategies, providing numerical and graphical results overall and per single patient. After 4–6 months of combination therapy, 5-fluorouracil/leucovorin (5-FU/LV) + bevacizumab or panitumumab was recommended in all studies except for the 50% of patients in the VALENTINO trial who received panitumumab alone. ResultsOut of 1400 patients included, 42% received FOLFOXIRI (5-FU/LV, oxaliplatin, and irinotecan)/bevacizumab, 18% FOLFIRI/bevacizumab, 24% FOLFOX/bevacizumab, 16% FOLFOX/panitumumab. Mean grade of general and haematological AEs was higher in the first cycles, then progressively decreasing after the end of induction (p < 0.001), and always remaining at the highest levels with FOLFOXIRI/bevacizumab (p < 0.001). Neurotoxicity became more frequent over the cycles with late high-grade episodes (p < 0.001), while the incidence but not the grade of hand-and-foot syndrome gradually increased (p = 0.91). Anti-VEGF-related AEs were more severe in the first cycles, then setting over at low levels (p = 0.03), while anti-EGFR-related AEs still affected patients during maintenance. ConclusionsMost of chemotherapy-related AEs (except for HFS and neuropathy) reach the highest level in the first cycles, then decrease, probably due to their active clinical management. Transition to maintenance allows relief from most AEs, especially with bevacizumab-based regimens, while anti-EGFR-related AEs may persist.

Effect of SGLT-2 inhibitors as an add-on therapy to metformin on P wave indices and atrial electromechanics in type 2 diabetes mellitus patients.

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors have been shown to reduce the risk of atrial fibrillation (AF) occurrence in patients with diabetes mellitus (DM). In this prospective study, we aimed to analyze the effect of SGLT-2 inhibitors as an add-on therapy to metformin on P wave indices and atrial electromechanics in patients with type 2 DM. A total of 144 patients enrolled. Electrocardiographic indices were recorded on admission and at 3rd and 6th month of the combination therapy. P wave indices and atrial electromechanical coupling intervals were measured and compared. Although decrease in P wave dispersion (62.78±9.59vs.53.62±10.65; p = .002) became significant at 6th month of combination therapy, significant decreases in P wave terminal force in V1 (37.79±3.45vs.32.01±5.74; p=.035), left atrial volume index (35.87±6.57vs.31.33±7.31;p=.042), left sided intra-atrial electromechanical delay (32.09±9.17vs.27.61±8.50;p=.016), right sided intra-atrial electromechanical delay (31.82±4.92vs.27.65±8.05;p=.042), and interatrial electromechanical delay (29.65±7.52vs.25.96±4.30;p=.044) were seen as early as 3rd month of treatment. Besides, there was no statistically significant difference between Empagliflozin and Dapagliflozin subgroups in terms of mentioned parameters. SGLT-2 inhibitors as an add-on therapy to metformin were shown to significantly improve P wave indices and atrial electromechanics in type 2 DM patients as early as the 3rd month of treatment. It was thought that this may be one of the underlying mechanisms of the decrease in the frequency of AF with the use of SGLT2 inhibitors.

Observational study of HR+/HER2− metastatic breast cancer patients treated with abemaciclib in Spain in the Named Patient Use Program (AbemusS)

Introduction/objectivesTo describe abemaciclib use in patients with hormone receptor-positive, human epidermal growth factor receptor-negative (HR+/HER2−) metastatic breast cancer (mBC) who participated in the Named Patient Use program (NPU) in Spain.Material and methodsThis retrospective study was based on medical record review of patients across 20 centers during 2018/2019. Patients were followed up until death, enrolment in a clinical trial, loss of follow-up or study end. Clinical and demographic characteristics, treatment patterns and abemaciclib effectiveness were analyzed; time-to-event and median times were estimated using the Kaplan–Meier (KM) method.ResultsThe study included 69 female patients with mBC (mean age 60.4 ± 12.4 years), 86% of whom had an initial diagnosis of early BC and 20% had an ECOG ≥ 2. Median follow-up was 23 months (range 16–28). Metastases were frequently observed in bone (79%) and visceral tissue (65%), with 47% having metastases in > 2 sites. Median number of treatment lines before abemaciclib was 6 (range 1–10). Abemaciclib monotherapy was received by 72% of patients and combination therapy with endocrine therapy by 28% of patients; 54% of patients required dose adjustments, with a median time to first adjustment of 1.8 months. Abemaciclib was discontinued in 86% of patients after a median of 7.7 months (13.2 months for combination therapy and 7.0 months for monotherapy) mainly due to disease progression (69%).ConclusionThese results suggest that abemaciclib is effective, as monotherapy and in combination, for patients with heavily pretreated mBC, consistent with clinical trial results.

P799 Infliximab and immunomodulator combination therapy in inflammatory bowel disease – no longer inseparable?

Abstract Background The gold-standard for prescribing Infliximab (IFX) in IBD is to use it in combination with an immunomodulator (IMM), thereby reducing the risk of immunogenicity and improving overall outcomes. This practice, however, comes with considerable increased risk of adverse events. There is mounting evidence that withdrawal of IMMs, especially after 6 months of combination therapy (CT), does not reduce IFX trough levels or increase the risk of loss of response (Drobne et al., 2015; Mahmoud et al., 2022). We identified IBD patients on IFX CT who were eligible to stop their IMM based on defined criteria and assessed clinical outcomes of patients who had previously had their IMM withdrawn. Methods This was a retrospective cross-sectional study in a central London tertiary hospital. We included patients with a diagnosis of Crohn’s Disease (CD), Ulcerative Colitis, or Indeterminate colitis, with therapeutic IFX levels &amp;gt;5mg/ml, undetectable anti-drug antibodies (ADA) (&amp;lt;10 AU/ml) and at least 6 months of CT from induction between January 2017 and December 2021. Patients were identified on an immunology laboratory database and electronic patient records were manually assessed for baseline characteristics and clinical outcomes. The primary timepoint of interest for clinical outcomes is 4 months after measurement of IFX drug levels. Results A total of 825 IBD patients had IFX drug levels performed in the defined time-period. 296 patients had IFX levels &amp;gt;5mg/ml and undetectable ADAs; of these 160 (54%) had been on CT for &amp;gt;6 months. Baseline characteristics were 41.3% (n=66) female, mean age (y) of 29 (SD ±14) and 70.6% (n=113) had CD. In the 4 months after IFX drug assays, 140 of 160 (87.5%) patients remained on CT whereas 20 (12.5%) had previously stopped their IMM. Of those on CT, 90.7% (127/140) were in clinical remission at the time of the assay compared to 90% (18/20) of patients in the IMM withdrawal group (p=0.46). At the time of data collection, 79.3% (111/140) of CT patients remained on IFX therapy compared to 75% (15/20) who withdrew IMMs (p=0.33, median follow up 19 months). IMM withdrawal was predominantly due to side effects (n=16, 80%) with the remainder due to clinical remission (n=4, 20%). The 2/20 (10%) patients with active disease in the IMM withdrawal group were active prior to stopping IMMs. Conclusion Patients with good IFX drug levels and undetectable ADAs after at least 6 months of IFX CT did well regardless of whether they withdrew IMMs or not, supporting recent studies that suggest it is safe to do so. Given the number of our patients who could potentially benefit from stopping their IMMs, prospective controlled studies are required to determine whether this is advisable given the theoretical risk of loss of response.

Treatment Free Remission after Combination Therapy with Asciminib (ABL001) Plus Imatinib in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed after a Prior Attempt at TKI Discontinuation-H Jean Khoury Cure CML Consortium Study

Successful tyrosine kinase inhibitor (TKI) discontinuation is currently one of the main goals of CML therapy. Patients who are in sustained deep molecular remission can attempt TKI discontinuation; approximately 50% of such patients will achieve a successful treatment free remission (TFR) and the other 50% will have molecular recurrence , warranting reinitiation of TKI therapy. Molecular recurrence is defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) . With a goal to increase the ultimate fraction of successful TFR, inquiry has begun into the rate and optimal approach to TFR after a second attempt at TKI discontinuation in patients with molecular recurrence after their first attempt. Molecular recurrence, is suspected to be driven by CML progenitor element(s) capable of, permitted to, and/or signaled to proliferate; different approaches to eradicate such a compartment have been proposed. One such potential means may be through alternative and synergistic BCR::ABL1 inhibition with the allosteric inhibitor asciminib in combination with approved TKIs for CML. Asciminib is a potent BCR::ABL1 inhibitor with a novel, allosteric mode of action. The activity of asciminib is a result of its ability to bind a vacant pocket on the kinase domain that is normally occupied by the myristoylated N-terminus of ABL, a negative regulatory element lost upon the fusion of ABL to BCR. Asciminib has an excellent selectivity profile, is several-fold more potent than current approved TKIs such as nilotinib, and in vitro was active in the low nanomolar range against a spectrum of clinically observed ATP site mutations. Asciminib demonstrated efficacy in phase I studies in resistant/intolerant chronic and accelerated phase CML, including T315I mutation positive and ponatinib pretreated patients. In a phase III trial, asciminib was more active than bosutinib in a phase III trial in patients who had received 2 prior TKIs Our primary objective in this study is to determine the 1-year TFR rate after 12 months of combination therapy with imatinib plus asciminib, followed by treatment cessation, in subjects who have previously had molecular recurrence first TFR attempt. This is a single arm phase II study that will enroll a maximum of 51 patients (NCT04838041). All subjects will have a confirmed diagnosis of CML-CP. Each subject must have previously attempted to discontinue imatinib, and were restarted on imatinib at the time of molecular recurrence in order to be eligible for this trial. This trial will use asciminib 40 mg PO daily plus imatinib at a maximum dose of 400 mg PO once daily in the combination treatment phase of this trial. All eligible subjects will be treated with asciminib and imatinib on cycle 1 day 1 of the combination therapy phase. Patients will remain on imatinib for 12 cycles. RQ-PCR to measure BCR::ABL1 transcripts in the peripheral blood at screening and at specific time points during the first 12 cycles on trial (combination therapy phase). At the end of 12 cycles, asciminib and imatinib will be discontinued in any subject who has continued in stable deep remission and thus meets criteria for TFR. This study will assess a wide range of PROs before and after stopping imatinib. These will be done in conjunction with RQ-PCR testing, though at fewer time points, utilizing online and/or phone questionnaires. The alternative hypothesis of relapse rate after second discontinuation of TKI combination treatment is 35% will be tested against a one-sided alternative of historical control of 55% relapse rate. Simon's two-stage admissible design will be used. The null hypothesis that the true TFR rate (no loss of MMR) is 45% will be tested against a one-sided alternative. In the first stage 29 patients will be accrued. If there are 15 patients or fewer who maintain TFR in these 29 patients, the study will be stopped. Otherwise, 18 additional patients will be accrued for a total of 47. The null hypothesis will be rejected if 27 or more patients maintain TFR in 47 patients. This design yields a type I error rate of 5% and power of 85% when the true TFR rate is 65%. To account for a potential dropout rate of 8% due to adverse events or loss of response, 51 patients will be enrolled to achieve the 47 patients needed.

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 4-Year Follow-up Data

Background: Ibrutinib (IBR) and venetoclax (VEN) combination is an effective therapy for patients (pts) with CLL. We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019, JAMA Oncology 2021). Here we report updated data for 120 pts (80 pts in the original published cohort and 40 pts in an expansion cohort) with a median follow-up of 4 years. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years. Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and IBR for pts who remained BM MRD+ after Cycle 24. Response assessments included BM and CT studies (2008 IWCLL criteria). U-MRD was defined as <0.01%; low MRD+ 0.01% to <1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months after active therapy. Results: Between August 2016 and February 2019, a total of 120 pts were enrolled. Baseline characteristics are shown in Table 1. The median follow-up is 48.8 months. Six pts came off study during 1st 3 cycles of IBR monotherapy; 114 pts initiated VEN. After 12 cycles of the combination, 62/120 (52%) achieved BM U-MRD remission; 43/120 (36%) were BM MRD-positive (low MRD+, n=35; high MRD+, n=8). After 24 cycles of the combination, 77/120 (64%) achieved BM U-MRD remission; 24/120 (20%) were BM MRD+ (low MRD+, n=23; high MRD+, n=1). Overall, 86/120 (72%) achieved BM U-MRD as the best response. We evaluated baseline pt and disease characteristics (age, gender, IGHV mutation status, CLL FISH panel, complex karyotype, TP53 mutation, del(17p)/TP53 mutation) and rate of bone marrow U-MRD at 6 months, 12 months and at any time during the combined IBR+VEN treatment. At 6 months of combined therapy, presence of TP53 mutation was associated with a lower rate of bone marrow U-MRD (p=0.03); however, none of the aforementioned characteristics, including TP53 mutation were associated with marrow U-MRD responses at 12 months or with best MRD response at any time during the combined therapy. There was a trend towards lower U-MRD rate among pts with mutated IGHV vs. unmutated IGHV at 12 month (p=0.09) and as best response (p=0.09). The 4-year PFS is 94.5% (95% CI, 90.3%-98.9%) and 4-year OS is 96.6% (95% CI, 93.3%-99.9%). The 4-year PFS by TP53 aberrant status is shown in Figure 1. The 4-year PFS for pts with del(17p)/TP53 mutation (n=27) is 90.9% and for pts without del(17p)/TP53 mutation (n=93) is 95.5%. None of the aforementioned pt/disease characteristics were associated with PFS. Of the 77 pts who were BM U-MRD at the end of cycle 24 of the combination, 73 discontinued all therapy, 4 pts continued IBR per treating physician discretion. Among these 77 pts, with a median time of 23.9 months post Cycle 24, 11 pts had recurrence of blood MRD (defined as MRD ≥0.01% in 2 consecutive visits). Of the 11 pts with MRD recurrence, 10 are being monitored without any active therapy for CLL and without clinical disease progression; 1 pt had disease progression after 22 months of treatment-free interval and is currently receiving acalabrutinib. There were 24 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=23; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 23 pts (all low MRD+ in BM, range 0.01-0.95%) continued IBR monotherapy. With a recent trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of VEN; 18/23 pts have resumed VEN. 11/18 (61%) pts achieved U-MRD remission during the third year of combined therapy. Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 4-year PFS of 94.5%. MRD responses and PFS were independent of baseline pt/disease characteristics. Continuation of combined therapy among marrow MRD+ pts during the second and the third year led to achievement of U-MRD in a subset of pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Isolated adrenocorticotropic hormone deficiency associated with sintilimab therapy in a patient with advanced lung adenocarcinoma: a case report and literature review

BackgroundSeveral immune checkpoint inhibitors have been implemented for cancer treatment which have shown some degree of antitumor effcacy, while immune-related adverse events (irAEs) that affect multiple organ functions ensue which obviously should not be neglected. Though less common than other kinds of irAEs, Immune checkpoint inhibitors (ICIs) related Isolated ACTH deficiency (IAD) may cause long-term damage to pituitary-adrenal axis. Several case reports are available about IAD during anti-PD-1 therapy. We report the first case of immune checkpoint inhibitor-induced IAD following 3 month of sintilimab therapy.Case presentationA 66-year-old Chinese man was diagnosed with stage IIIB lung adenocarcinoma with involving ipsilateral intrapulmonary and hilar lymph node metastasis. After 3 months of combination therapy of nedaplatin, pemetrexed and sintilimab, the patient presented with general fatigue, nausea and vomiting. Laboratory investigation at admission revealed hyponatremia and hypokalemia. Further investigation revealed adrenocorticotropic hormone and cortisol levels were far below than normal limits. His other pituitary hormone levels were normal, except for mild elevation of follicle stimulating hormone and estradiol. Cranic magnetic resonance imaging showed a normal pituitary gland. Isolated adrenocorticotropic hormone deficiency was diagnosed, and corticosteroid replacement therapy was administered, leading to a significant improvement of his symptoms while ACTH level maintaining low level.ConclusionsOur patient developed isolated ACTH deficiency during combination cancer treatment with chemotherapy and sintilimab. Although isolated ACTH deficiency due to anti-PD-1 including sintilimab therapy is rare occurrence, it can often cause severe clinical symptoms. Its diagnosis basically relies on clinical symptoms and endocrinological examination. Unlike traditional hypophysitis diagnosed by cranial MRI, pituitary MRI of IAD due to anti-PD-1 often indicates normal pituitary gland implying that over-reliance on imaging findings is not recommended. Even if clinical symptoms have relieved after corticosteroid replacement therapy was commenced, low levels of ACTH or cortisol could maintain for a long period which highlights the need for long term corticosteroid therapy. The purpose of the current report was to provide increased awareness of early detection and therapy of IAD.

LGG-42. Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy

INTRODUCTION: Event-free survival of pediatric low-grade glioma (pLGG) is poor, and patients often require multiple treatment strategies. The hallmark of pLGGs are genetic aberrations of the mitogen-activated protein kinase pathway, which lead to constitutive pathway activation. MEK and RAF inhibitors target this pathway and are efficacious in early phase trials in recurrent pLGGs. However, not all patients respond to monotherapy, and many experience progression after completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. Lenalidomide is an immunomodulatory agent with an anti-tumor effect demonstrated in phase 1 trials in recurrent pediatric central nervous system (CNS) tumors. OBJECTIVE: To describe our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system (PNS) tumors. METHODS: Retrospective review of patients’ medical records. RESULTS: Four patients with locally recurrent primary CNS or PNS tumors, three with WHO grade II pilomyxoid astrocytomas and one with a plexiform neurofibroma, were treated with trametinib and lenalidomide concurrently. Two patients developed severe thromboembolic events. One patient was treated with combination therapy for seven months until trametinib and lenalidomide were held after urgent ventriculoperitoneal shunt revision. Shortly following shunt revision, he experienced near-complete vision loss. MRI of the brain demonstrated a left posterior watershed territory hypoxic-ischemic injury. In a second patient, after four months of combination therapy, surveillance echocardiogram showed an incidental finding of severe biventricular dysfunction with a left ventricular ejection fraction (LVEF) of 17.7% and two mural thrombi in the left ventricular apex. She started losartan and enoxaparin and discontinued trametinib and lenalidomide. Her LVEF normalized four months later, and the mural thrombi resolved. CONCLUSIONS: Given the severe thromboembolic events experienced by these patients treated with concomitant trametinib and lenalidomide, this combination requires further investigation, and we urge caution if used concurrently.

Treatment paradigms and survival outcomes in esophageal adenocarcinoma with liver metastasis: a retrospective cohort study using the SEER database.

Esophageal adenocarcinoma with liver metastasis (EACLM) at the time of diagnosis has a poor prognosis and few therapeutic options. The best treatment options and prognostic factors for EACLM patients are unclear. The present study sought to explore the optimal treatment modalities for and the prognosis of these patients. Patients diagnosed with EACLM at the time of diagnosis were identified from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2015. The last follow-up date was December 31, 2018. Treatment patterns were divided into four groups: local therapy (surgery/radiation), systemic therapy [chemotherapy (CT)], combination therapy (surgery/radiation + CT), and no treatment. The Kaplan-Meier (K-M) method and log-rank test were used for overall survival (OS) and disease-specific survival (DSS). Univariable and multivariable Cox regression were performed to identify the prognostic factors. Propensity score-matching (PSM) analyses were performed for sensitive analyses. A total of 925 patients diagnosed with EACLM were included in the study. The median OS was 12, 10, 3, and 2 months for combination therapy, systemic therapy, local therapy, and no treatment, respectively (P<0.001). After PSM, the patients who received systemic treatment had a better OS (median 9 vs. 2 months; P<0.001) and DSS (median 9 vs. 3 months; P<0.001) than those who received no treatment. Compared to systemic therapy, combination therapy did not increase patients' OS (median 13 vs. 12 months, P=0.069) but did improve their DSS (median 19 vs. 13 months, P=0.048). EACLM patients might benefit the most from systemic therapy and combination therapy. For patients who are well-tolerated, combination therapy should be considered as a preferable option.

The beneficial effect of csDMARDs co-medication on drug persistence of first-line TNF inhibitor in rheumatoid arthritis patients: data from Czech ATTRA registry

The study aimed to compare treatment retention for first-line TNF inhibitor (TNFi) in the ATTRA registry patients receiving either combination with conventional synthetic DMARDs or TNFi as monotherapy. A retrospective multicenter study analyzed data of all adult patients with rheumatoid arthritis (n = 3032) starting TNF inhibitor as the first-line biological therapy in combination with csDMARDs or in monotherapy from January 1st 2012 to December 31st 2020. Kaplan–Meier method was employed to calculate drug retentions. Survival curves of treatment retentions were compared through Log-rank test between the studied subgroups. The hazard ratio for drug discontinuation was assessed through univariate cox regression models. In patients who started the first line TNFi therapy, the median treatment retention was 47.7 (42.2; 53.1) months for combination therapy and 22.7 (14.9; 30.6) months for TNFi monotherapy (p < 0.001). Estimated one-year survival was higher in patients on TNFi combined with csDMARDs as compared with TNFi monotherapy (75.3% vs 65.7%); two-year survival rate was 63.2% vs 49.2%, three-year survival rate was 55.4% vs 42.4% and five-year survival 44.9% vs 26.4% of patients. The estimated survival on the first TNFi was higher in patients taking combination therapy with methotrexate than with other csDMARDs (p = 0.003). Use of csDMARDs co-medication was associated with significantly better first TNFi drug survival compared to monotherapy. The combination of TNFi with MTX is more effective than the combination with leflunomide, which did not demonstrate a significant effect.

Evaluation of the effectiveness of thyrostatics in the treatment of comorbid patients with thyrotoxicosis

Objective: to evaluate the effect of thyrostatics on clinical symptoms, the frequency of cardiac arrhythmias and morpho-functional parameters of the left heart in patients with a combination of thyrotoxicosis and ischemic heart failure. Materials and methods: 85 patients participated in the study. Group 1st — patients with CHF of functional class II-III (FC) on the background of coronary heart disease and concomitant thyrotoxicosis (n=40), average age 58.6±4.6 years; group 2nd — patients with manifest thyrotoxicosis without cardiovascular pathology (n=45), average age 46.7± 4.1 years. When included in the study and after 6 months of therapy with the addition of thyrostatics, the clinical condition of patients and physical activity were evaluated, daily monitoring of an electrocardiogram and an echocardiographic study (EchoCG) were performed. Results: after 6 months of combined therapy with the inclusion of thyrostatics against the background of persistent drug-induced euthyroidism, exercise tolerance increased in comorbid patients (group 1) (p&lt;0.001), the severity of clinical symptoms of CHF decreased, and the frequency of cardiac arrhythmias significantly decreased (p&lt;0.05). The analysis of the dynamics of EchoCG results in group 1 patients revealed a significant increase in the index of shock ejection (p=0.04), left ventricular ejection fraction (p=0.01), shock volume (p=0.03), a decrease in the value of myocardial stress (p=0.02) and parameters characterizing the transmittal flow (E/A, p&lt;0.05), which allowed us to judge the improvement of systolic and diastolic function of the left ventricle (LV) under conditions of drug compensation thyrotoxicosis. Conclusion: the inclusion of thyrostatics in combination therapy and normalization of thyroid function contributed to the reduction of clinical symptoms of heart failure, the frequency of cardiac arrhythmias, improvement of systolic and diastolic LV function in comorbid patients with ischemic CHF and concomitant thyrotoxicosis.