Cumulative Illness Rating Scale Score Research Articles

Total laryngectomy and readmission: causes, rates and predictors

BackgroundTotal laryngectomy (TL) is a complex procedure, and patients undergoing TL are at high risk for readmission, which exposes them to hospital-acquired complications. Readmission rate is a metric for quality of care. We aimed to identify the rate, causes, and predictors of hospital readmission within 60 days after discharge following TL.MethodsThis is a 12-year retrospective study where we included all patients undergoing TL in a single tertiary care center between 2008 and 2022. Patient charts were reviewed for demographics, comorbidities, and causes for readmission.ResultsOf 83 patients who underwent TL, 12 (14.50%) were readmitted within 60 days. Common causes were surgical site infection (33.33%) and mucocutaneous fistula (25%). Significant predictors for readmission were tobacco use (P = 0.003), African ethnicity (P = 0.004), being unmarried (P < 0.001), lower preoperative serum albumin (P < 0.001), higher preoperative TSH (P = 0.03), higher preoperative neutrophil count (P = 0.035), higher American Society of Anesthesiology (ASA) score (P = 0.028), and higher Cumulative Illness Rating Scale (CIRS) score (P = 0.029).ConclusionOne in every seven patients were readmitted following TL. Frequent causes include wound infection and fistulas. Predictors include preoperative hypoalbuminemia, hypothyroidism, African ethnicity, being unmarried, tobacco use, and a higher baseline burden of comorbidities. Such factors can be targeted to reduce hospital readmission rates.

The Role of the Cumulative Illness Rating Scale (CIRS) in Estimating the Impact of Comorbidities on Chronic Obstructive Pulmonary Disease (COPD) Outcomes: A Pilot Study of the MACH (Multidimensional Approach for COPD and High Complexity) Study.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous systemic syndrome that often coexists with multiple comorbidities. In highly complex COPD patients, the role of the Cumulative Illness Rating Scale (CIRS) as a risk predictor of COPD exacerbation is not known. The objective of this study was determine the effectiveness of the CIRS score in detecting the association of comorbidities and disease severity with the risk of acute exacerbations in COPD patients. In total, 105 adults with COPD (mean age 72.1 ± 9.0 years) were included in this prospective study. All participants at baseline had at least two moderate exacerbations or one leading to hospitalization. The primary outcome was a composite of moderate or severe COPD exacerbation during the 12 months of follow-up. The CIRS indices (CIRS total score, Severity Index and Comorbidity Index) showed a positive correlation with modified Medical Research Council (mMRC), COPD assessment test (CAT) and a negative correlation with forced expiratory volume in the first second (FEV1), Forced Vital Capacity (FVC), and FEV1/FVC. The three CIRS indices were able to predict the 12-month rate of moderate or severe exacerbation (CIRS Total Score: Hazard Ratio (HR) = 1.12 (95% CI: 1.08-1.21); CIRS Severity Index: HR = 1.21 (95% CI: 1.12-1.31); CIRS Comorbidity Index = 1.58 (95% CI: 1.33-1.89)). Among patients with COPD, the comorbidity number and severity, as assessed by the CIRS score, influence the risk in moderate-to-severe exacerbations. The CIRS score also correlates with the severity of respiratory symptoms and lung function.

First-Line Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O): 55-Month Follow-up from the Glow Study

Introduction : In the GLOW trial (NCT03462719), fixed-duration Ibr+Ven treatment has shown superiority to Clb+O in progression-free survival (PFS), better sustained undetectable minimal residual disease (uMRD) responses, and overall survival (OS) benefit in patients with previously untreated chronic lymphocytic leukemia (CLL) who are older and/or have comorbidities (CU Niemann, et al. Blood. 2022;140[suppl 1]:228-230). In this analysis, we report clinical outcomes, including PFS, OS, and MRD analysis, from the Ibr+Ven combination in GLOW with a median follow-up of 55 months, including subgroup analyses by IGHV and MRD. Methods : Patients aged ≥ 65 years or 18 to 64 years with a Cumulative Illness Rating Scale score &amp;gt; 6 or creatinine clearance &amp;lt; 70 mL/min were randomized 1:1 to Ibr+Ven (3 cycles of Ibr lead-in, followed by 12 cycles of Ibr+Ven; N = 106) or 6 cycles of Clb+O (N = 105). Each cycle was 28 days. Patients were excluded if they had del17p or known TP53 mutations at screening. End points included investigator-assessed PFS, uMRD rates, time to next treatment (TTNT), and OS. MRD was assessed sequentially over time in peripheral blood by next-generation sequencing for patients with partial response (PR) or better. Patients with &amp;lt; 1 CLL cell per 10,000 leukocytes (&amp;lt; 10 -4) were considered to have uMRD, whereas patients with ≥ 1 CLL cell per 10,000 leukocytes (≥ 10 -4) were considered to have detectable MRD (dMRD). All p values reported were nominal. Safety was not further assessed, as all patients were already past the treatment period in previous analyses. Results of updated analyses : With a median follow-up of 55 months, PFS remained superior for Ibr+Ven (hazard ratio [HR] 0.239 [95% confidence interval (CI), 0.159-0.359]; p &amp;lt; 0.0001); 54-month PFS rates were 65.8% for Ibr+Ven and 19.1% for Clb+O. In the Ibr+Ven arm, for patients with unmutated IGHV (uIGHV; n = 67) and mutated IGHV (mIGHV; n = 32), 54-month PFS rates were 58% and 90%, respectively. Also in the Ibr+Ven arm, PFS rates at 3 years post-treatment were 82% in patients who achieved uMRD at 3 months after end of treatment (EOT+3; n = 58) and 73% for patients with dMRD (n = 31). Among patients with uIGHV, PFS rates at 3 years post-treatment were 81% for those achieving uMRD at EOT+3 (n = 40) and 56% for those with dMRD (n = 16). In patients with mIGHV, PFS rates at 3 years post-treatment were ≥ 92% regardless of MRD status at EOT+3. Overall, at 38 months after end of treatment (EOT+38), 32.1% of patients had uMRD in the Ibr+Ven arm. Of the patients who achieved uMRD at EOT+3 (n = 58), 53.4% sustained uMRD status at EOT+38 in the Ibr+Ven arm. In addition, TTNT was prolonged for patients receiving Ibr+Ven versus Clb+O. The risk of needing second-line therapy was significantly reduced by 83% with first-line Ibr+Ven versus Clb+O (HR 0.174 [95% CI, 0.088-0.342]; p &amp;lt; 0.0001), and by 85% among patients with uIGHV (HR 0.146 [95% CI, 0.069-0.310]) compared with a 29% risk reduction in those with mIGHV (HR 0.708 [95% CI, 0.118-4.256]). In the Ibr+Ven arm, 4 patients received single-agent ibrutinib as subsequent therapy as part of the study; while 1 patient had not yet had a disease assessment, the best response for the other 3 patients were complete response (n = 1) and PR (n = 2). Finally, Ibr+Ven continues to demonstrate improved OS versus Clb+O, reducing the risk of death by 58% (HR 0.421 [95% CI, 0.237-0.747]; p = 0.0023). Estimated 54-month OS rates were 84.5% for the Ibr+Ven arm and 63.1% for the Clb+O arm. Conclusion : With prolonged follow-up of 55 months in the GLOW study, all-oral, once-daily, fixed-duration Ibr+Ven continues to show superior PFS versus Clb+O. Among patients treated with Ibr+Ven, benefit in PFS was particularly observed in patients with uIGHV who achieved uMRD at EOT+3 and in patients with mIGHV regardless of MRD status at EOT+3. Moreover, Ibr+Ven fixed-duration combination treatment continues to demonstrate an OS advantage versus chemoimmunotherapy in patients with previously untreated CLL.

Brentuximab Vedotin in Frontline Therapy of Hodgkin Lymphoma in Patients with Significant Comorbidities Ineligible for Standard Chemotherapy (SGN35-015 Part E)

Brentuximab vedotin (BV) is approved for the treatment of adults with treatment-naïve stage III or IV classical Hodgkin lymphoma (cHL) combined with doxorubicin, vinblastine, and dacarbazine (AVD) and targets CD30, a receptor expressed on the Reed Sternberg cells. Treatment with BV plus AVD has demonstrated improved overall survival (OS) (6-year OS estimate of 93.9% vs 89.4%; HR, 0.59; 95% CI, 0.40-0.88; P=0.009) compared with the standard chemotherapy combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (Ansell 2022). For patients (pts) newly diagnosed with cHL, current treatment options have improved pt outcomes in recent years, but survival rates are still very low for those with significant comorbidities. Pts with comorbid conditions can have poor outcomes due to decreased ability to tolerate dose intensity, increased treatment-related toxicity, and cHL relapse. This study is evaluating the efficacy and safety of single-agent BV as frontline therapy in cHL pts who are ineligible for conventional combination chemotherapy because of comorbidities. SGN35-015 Part E (NCT01716806) was a phase 2, open-label study of BV as frontline cHL therapy. Eligible pts (≥18 years) were unfit for initial conventional combination chemotherapy for cHL as documented by a modified Cumulative Illness Rating Scale score ≥10 or because they required or depended on others for instrumental activities of daily living. Pts received BV (1.8 mg/kg) on Day 1 of each 3-week cycle for up to 16 cycles. Granulocyte colony-stimulating factor prophylaxis was not required. The primary endpoint, objective response rate (ORR), was assessed by Blinded Independent Central Review (BICR) according to the Modified Lugano Criteria (Cheson 2014). Key secondary endpoints included safety, duration of response (DOR), complete response (CR) rate using the Lugano Criteria (Cheson 2014), duration of CR, progression-free survival (PFS), and OS. Thirty pts with cHL received BV and the median age was 76 years (range, 54 to 93 years). Most pts were female (53%) and had a disease stage of II (37%) or III (37%), an Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 (50%; 10 pts [33%] and 5 pts [17%] had an ECOG performance status of 2 and 3, respectively). The median treatment duration was 18 weeks (range, 1 to 50 weeks). Per BICR, the ORR was 60% (18/30) (95% CI: 40.6%, 77.3%), including 33% (10/30) with a CR and 27% (8/30) with a partial response. Six pts (20%) did not respond to treatment: 1 (3%) with progressive disease and 5 (17%) with stable disease; one pt (3%) was not evaluable and the remaining 5 pts (17%) did not have postbaseline responses, either because of death before first scheduled response assessment or not yet reaching the first scheduled response assessment. Median DOR was 7.4 months (95% CI: 7.4 months, not estimable) and median PFS was 8.7 months (95% CI: 5.1 months, not estimable). Median duration of CR was not estimable (95% CI: 7.4 months, not estimable). With a median follow-up of 14.6 months (range, 0 to 44 months), the 2-year OS rate was 70% (95% CI: 48%, 84%). A total of 18 pts (60%) experienced grade ≥3 treatment-emergent adverse events (TEAEs). The most common grade ≥3 TEAEs were fatigue (n=3; 10%), acute kidney injury, anemia, atrial fibrillation, back pain, gait disturbance, hypoxia, neutrophil count decreased, pneumonia, sepsis, syncope, and vomiting (n=2 each; 7%). Nine pts (30%) discontinued treatment because of a TEAE; 1 death due to a TEAE (failure to thrive) was considered treatment-related. Thirteen percent (n=4) of pts experienced grade ≥3 peripheral neuropathy. In pts with cHL who are unfit for initial conventional chemotherapy due to comorbidities, BV monotherapy as frontline treatment appears effective, has an acceptable safety profile, and despite the small sample size could be considered as an option for pts with cHL who are unfit for conventional chemotherapy.

A Multicenter Retrospective Study to Understand the Clinical Characteristics, Treatment Patterns, and Resource Utilization for Patients with Chronic Lymphocytic Leukemia: CREEK Study

Abstract Introduction: The ever-growing array of treatments available for chronic lymphocytic leukemia (CLL) led to a significant change in CLL management over the last few years. However, information about managing CLL is scattered across various regions, resulting in significant disparities in treatment approaches and patient outcomes between countries. The CREEK study aimed to describe the disease characteristics, treatment patterns, and overall survival (OS) among CLL-treated (CLL-Tx) patients and CLL treatment-naïve (CLL-N) patients in different regions. Methods: Data from 1009 patients were collected retrospectively from June 2016 to March 2023. This observational study included 886 CLL-Tx patients from 17 countries in the Middle East and Africa (MEA), Asia Pacific (AP), and Latin America (LA); and a pilot cohort of 123 CLL-N patients from the Gulf Cooperation Council (GCC) countries. Patients' demographics, disease characteristics, laboratory assessments, comorbidities, treatment patterns, treatment-related adverse events (AEs), OS, and medical resource utilization (MRU) data were recorded. Results: The average age for both cohorts was 63 years. Most patients were males, 66.7% in CLL-Tx and 69.9% in CLL-N. The mean duration from clinical manifestation until diagnosis was 21.37 months for CLL-Tx and 1.46 months for CLL-N patients (p&amp;lt;0.0001). For CLL-Tx, almost 62% of the patients in MEA, 59.3% in AP, and 68.8% in LA had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, and similarly for CLL-N patients (56.1%). Total leucocytic count, lymphocytes, and platelets showed a significant difference (p&amp;lt;0.05) between CLL-Tx and CLL-N patients. As per the Cumulative Illness Rating Scale (CIRS), musculoskeletal (p&amp;lt;0.0008) and endocrine-metabolic (p&amp;lt;0.0001) comorbidities were more frequent in the CLL-Tx group. Regarding the CLL-Tx patients, 69.7%, 62.9%, and 41.1% had extremely severe hematological problems (CIRS score 4) in MEA, LA, and AP, respectively. At diagnosis, patients from the MEA region presented with the highest prevalence of advanced disease staging, with 44.8% and 35.3% based on Rai and Binet Staging Scores, respectively; moreover, CLL-Tx patients exhibited a more advanced staging compared to CLL-N based on the same scores (p &amp;lt;0.0001). FISH testing for disease prognosis was not performed in about 59% of the patients across all regions. The testing rates for cytogenetic abnormalities, IGHV mutation status, and TP53 aberrations were relatively low in all regions. The percentage of unmutated IGHV was considerably higher (p=0.0001) in CLL-Tx (15.6%) patients, with the highest percentage in LA (21.0%), compared to CLL-N (10.6%). Cytogenetic abnormalities did not show significant differences between CLL-Tx and CLL-N patients (p&amp;gt;0.05), while TP53 aberrations differ significantly (p&amp;lt;0.05) (Table 1). Most patients, 76.0%, 81.8%, and 69.4%, received chemo-immunotherapies as 1 st line therapy, while 18.3%, 17.1%, and 30.1% received targeted therapy in MEA, AP, and LA, respectively. The percentage of patients with AEs who received 1 st line chemo-immunotherapies was higher than those who received targeted therapy (25.6% vs. 7.3%). The mean OS was 153.89 months in the treated study population (Table 2). The mean number of inpatient hospitalizations was 1.9 times for chemo-immunotherapy and 0.8 times for targeted therapy. The mean lengths of stay of 14.9 and 13.9 days, respectively; mean emergency room visits were 0.5 and 0.7, and blood transfusions were received by 16.7% and 9.2% of patients, respectively. Conclusions: This study highlights the variable disease characteristics between CLL-Tx and CLL-N patients and provides insight into the regional variations in treatment patterns and OS for CLL-Tx patients. A considerable number of patients had advanced disease staging at diagnosis; however, the study showed relatively low genetic testing rates, indicating the need for adequate clinical watchfulness. Despite being in the era of approved targeted therapy, the utilization of chemo-immunotherapy continues to be higher than that of targeted therapy in the first line, probably due to the lower access to targeted therapies. Keywords: Chronic Lymphocytic Leukemia (CLL), Genetic Testing, Treatment Patterns, Targeted Therapy, Chemo-immunotherapy, Real World Data.

Frailty Impact on Outcomes of Patients Undergoing Chimeric Antigen Receptor T-Cell (CAR T) Therapy at Princess Margaret Cancer Centre: A Prospective Pilot Study

Introduction Princess Margaret Cancer Centre is 1 of 3 adult centres in Ontario, Canada providing Chimeric Antigen Receptor T-Cell (CAR T) therapy as a standard of care treatment for adult patients with relapsed and refractory B-cell lymphomas. There is no upper age limit for treatment consideration, and frailty may be an important factor in assessing fitness for treatment. This study aims to determine if frailty assessments pre-CAR T can predict those at higher risk for acute toxicities, PFS, and OS, as well as evaluate changes in frailty over time. Methods We performed a cohort study of consecutive patients with lymphoma undergoing CAR T cell therapy at our institution, from April 2021 to date. Frailty was evaluated using the Clinical Frailty Scale (CFS), Grip Strength, Gait Speed, Mini-Cog, Edmonton Symptom Assessment System (ESAS) and Patient Health Questionnaire (PHQ-2 and PHQ-9) at 5 time points: baseline (clearance visit), and 1, 3, 6 and 12 months post-CAR T. At baseline, additional assessments were completed to further characterize frailty including the Vulnerable Elders Survey (VES-13), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and Cumulative Illness Rating Scale (CIRS). We present data on patients enrolled to date. Results Fifty-two patients have had their data analyzed thus far. Mean age is 57.9 ± 12.7 years and 54% are male. 50% have de novo diffuse large B-cell lymphoma, 24% transformation from follicular lymphoma,14% HGBCL, 6% PMBCL and 6% FL. Most patients (83%) received axi-cel. Median follow-up is 3.80 months (IQR 0.56-24.7 mo). All 52 patients completed assessments at baseline, 44 completed 1 month, 25 completed 3 month, 12 completed 6 month and 11 completed 12 month assessments. Median scores (and IQR) for the HCT-CI, CIRS, VES-13 and CFS at baseline were 1.5 (0-5), 3.0 (0-13), 1.0 (0-7), and 3.0 (1-7) respectively. There were clinically significant changes observed in CFS over time ( p=&amp;lt;0.001), with mean scores of 3.3 at baseline, 3.7 at 1 month, 2.8 at 3 months and 2.1 at 12 months. There were no significant changes ( p=0.051; p=0.078) between timepoints for either of the physical assessments of grip strength or gait speed. Sixteen patients (31%) experienced immune effector cell neurotoxicity syndrome (ICANS) (4% Grade 4, 4% Grade 3, 8% Grade 2, 15% Grade 1) and forty-nine patients (94%) experienced cytokine release syndrome (CRS) (2% Grade 3, 65% Grade 2, 27% Grade 1), during the 30 days following cell re-infusion. Seven patients (13%) were admitted to the ICU, with a median in-hospital length of stay for all 52 patients of 12.5 days (IQR 7.0, 99.0). None of the variables tested (age, sex, bridging therapy, LDH, CRP and frailty assessments) were significantly associated with the development or grade of CRS or ICANS. There have been 21 progression events and 18 deaths (6 without progression); 9 pts remain alive post-progression (Figure 1). On univariable analysis of baseline data, ECOG performance status, LDH level, and the VES-13 score were predictive of PFS, while ECOG, LDH, CRP, VES-13 score, CFS and the time to walk 4m were predictive of OS. The HCT-CI and CIRS score were not significantly associated with outcomes. On multivariable analysis of PFS, baseline VES-13 score (HR 1.17, p=0.04) and LDH (HR 1.002, p=0.05) remained significant. Multivariable analysis for OS was not performed due to insufficient number of events. Analyses incorporating repeated measures were performed, and on univariable analysis, the CFS, 4m walk test (s), LDH, VES-13 were significantly associated with PFS and the same variables and CRP were associated with OS (Table 1). On multivariable repeated measurements analyses, only the CFS was still associated with PFS, and CFS and LDH with OS (Table 1). Conclusions Conducting serial frailty assessments in patients undergoing CAR T therapy is feasible. The only longitudinal measurement of frailty found to have clinically significant changes between timepoints was the CFS, suggesting an element of reversible functional impairment related to patients' lymphoma. Within the limits of our sample size, baseline measures of frailty were not predictive of CRS or ICANS; the relationship of CFS change over time with PFS and OS may be indicative of lymphoma response. Enrollment is ongoing and data on larger number of patients with longer term follow-up are needed.

Zanubrutinib vs FCR in Fit Treatment-Naive Patients with Chronic Lymphocytic Leukemia: A Matching-Adjusted Indirect Comparison

Background: Fludarabine, cyclophosphamide, and rituximab (FCR) is the standard first-line therapy for fit (physically active, with no major health problems and normal renal function) treatment-naive patients with chronic lymphocytic leukemia (CLL) (Eichhorst et al. Ann Oncol. 2015). Due to the safety profile of FCR, including severe hematotoxicity, and severe infections, treatments with improved efficacy and safety are of interest (Hallek et al. Lancet. 2010; Fischer et al. Blood. 2016). Zanubrutinib, a highly specific and potent small-molecule inhibitor of Bruton tyrosine kinase, has been approved for treatment-naive patients with CLL. However, the comparative efficacy of zanubrutinib vs FCR in patients with CLL has not been investigated. Objective: The objective of this study was to determine the relative treatment effects of zanubrutinib vs FCR in fit treatment-naive patients with CLL. Methods: The CLL10 trial (NCT00769522; Eichhorst et al. Lancet Oncol. 2016) investigated FCR and bendamustine + rituximab (BR), while the SEQUOIA trial compared zanubrutinib to BR (NCT03336333; Tam et al. Lancet Oncol. 2022). Zanubrutinib and FCR were compared by means of an anchored matching-adjusted indirect comparison (MAIC) in which the BR arm of each trial served as a common comparator. Propensity score matching was conducted using patient-level data from SEQUOIA to adjust for differences between trial populations, per National Institute for Health and Care Excellence MAIC methods (Philippo et al. NICE DSU Technical Support Document 18. 2016). Progression-free survival (PFS), as assessed by the independent review committee, was then compared based on the matched patient populations. The selection of matching variables was based on literature review and consultation with clinical experts. As the indirect treatment comparison was anchored on the common comparator arm (BR), patient characteristics that are solely prognostic did not need to be incorporated. The core model included immunoglobulin heavy chain gene mutation, cytogenetic mutations (11q deletion), β2-microglobulin, Binet stage, and age. Geographic region, sex, creatinine clearance, Cumulative Illness Rating Scale (CIRS) score, Eastern Cooperative Oncology Group performance status (ECOG PS), and previous infections were tested in sensitivity analyses. Results: PFS was favorable with zanubrutinib vs FCR, and statistically significant differences were observed in the base case model (hazard ratio [HR], 0.41; 95% CI, 0.20-0.81; p-value=0.01). Sensitivity analyses showed significantly improved PFS with zanubrutinib when adding geographic region (HR, 0.43; 95% CI, 0.21-0.90; p-value=0.03), sex (HR, 0.44; 95% CI, 0.22-0.89; p-value=0.02), ECOG PS (HR, 0.30; 95% CI, 0.14-0.64; p-value&amp;lt;0.01), and previous infections (HR, 0.45; 95% CI, 0.22-0.93; p-value=0.03) to the base case set of matching variables. A sensitivity analysis incorporating CIRS (HR, 0.45; 95% CI, 0.16-1.24; p-value=0.12) showed only numerically favorable PFS with zanubrutinib, owing in part to the low effective sample size (ESS) in the expanded model. Similar results were obtained when creatinine clearance was added to the base case matching set of variables (HR, 0.52; 95% CI, 0.24-1.13; p-value=0.10). Conditional on the number of matching variables, ESS ranged from 174.1 in the core model to 64.05 in the analysis that included the CIRS score. Conclusion:Our findings suggest that zanubrutinib offers clinically meaningful benefits in PFS over FCR in fit treatment-naive patients with CLL. MAICs rely on reporting of relevant patient characteristics in published studies. In the current study, ZAP-70 methylation and TP53 mutation, which were considered treatment effect modifiers, were not reported in CLL10 and were not accounted for in the propensity model.

Refractory/Relapsed High-Grade B-Cell Lymphoma in the Elderly: A Special Therapeutic Challenge

BACKGROUND: According to the 2016 World Health Organization classification of lymphoid neoplasms, high- grade B-cell lymphoma (HGBL) is defined as a new category for aggressive diffuse large B-cell lymphomas (DLBCL), including DLBCL NOS as well. CASE REPORT: An 80-year-old patient was admitted because of an enlargement of the lymph node located in the right neck region. The patient underwent 6 cycles of R-CHOP, which is considered to be the standard treatment for non-Hodgkin lymphomas (NHL) DLBCL (NOS) CSII B “Bulky,” and he subsequently achieved complete remission (CR). A lymph node biopsy was performed, PH No. 12742/21, which revealed the following: LCA+, CD79 α CD20+, and CD5+, in approximately 50% of the cells, NHL DLBCL (NOS) was of GCB origin, etc. The international prognostic index risk score was 2, the cumulative illness rating scale score was 4. In addition, no bone marrow infiltration was reported. A COP-based chemotherapy protocol was administered, after which the evaluation showed disease relapse. Multi-slice spiral computed tomography (MSCT) follow-up showed an enlarged conglomerate of lymph nodes in all the neck levels. Dg: NHL DLBCL (NOS) CS IVB “Bulky” E (the hypopharynx). The echocardiography results were the following: (EF 50%, aortic insufficiency with MR1+, TR1+ of the aortic valve 3+). The patient was presented to the Consilium, who decided to apply the following therapy (Polatuzumab vedotin + Rituximab + Bendamustine). After III cycle of treatment, MSCT follow-up was performed. The patient gained weight, oral food intake was enabled, whereas the quality of life was significantly improved. CONCLUSION: The administration of ta treatment may be provided to elderly patients with relapsed HGBL.

A validated composite comorbidity index predicts outcomes of CAR T-cell therapy in patients with diffuse large B-cell lymphoma.

Chimeric antigen receptor T-cell therapy (CART) has extended survival of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, limited durability of response and prevalent toxicities remain problematic. Identifying patients who are at high risk of disease progression, toxicity, and death would inform treatment decisions. Although the cumulative illness rating scale (CIRS) has been shown to correlate with survival in B-cell malignancies, no prognostic score has been independently validated in CART recipients. We retrospectively identified 577 patients with relapsed/refractory DLBCL indicated for CART at 9 academic centers to form a learning cohort (LC). Random survival forest modeling of overall survival (OS) and progression-free survival (PFS) was performed to determine the most influential CIRS organ systems and severity grades. The presence of a severe comorbidity (CIRS score ≥ 3) in the respiratory, upper gastrointestinal, hepatic, or renal system, herein termed "Severe4," had the greatest impact on post-CART survival. Controlling for other prognostic factors (number of prior therapies, Eastern Cooperative Oncology Group performance status, BCL6 translocation, and molecular subtype), Severe4 was strongly associated with shorter PFS and OS in the LC and in an independent single-center validation cohort (VC). Severe4 was also a significant predictor of grade ≥3 cytokine release syndrome in the LC, while maintaining this trend in the VC. Thus, our results indicate that adverse outcomes for patients with DLBCL meant to receive CART can be predicted using a simplified CIRS-derived comorbidity index.

What are the predictors of change in multimorbidity among people with HIV? A longitudinal observational cohort study.

Multimorbidity is common among people living with HIV (PLWH), with numerous cross-sectional studies demonstrating associations with older age and past immunosuppression. Little is known about the progression of multimorbidity, particularly in the setting of long-term access to antiretrovirals. This study aims to determine factors predictive of change in multimorbidity in PLWH. People living with HIV who attended a regional HIV service were recruited to a consented observational cohort between September 2016 and March 2020. Demographic data, laboratory results and a Cumulative Illness Rating Scale (CIRS) were collected at enrolment and first clinical review of every subsequent year. Change in CIRS score was calculated from enrolment to February 2021. Associations with change were determined through univariate and multivariate linear regression. Of 253 people, median age was 58.9 [interquartile range (IQR): 51.9-64.4] years, 91.3% were male, and HIV was diagnosed a median of 22.16 years (IQR: 12.1-30.9) beforehand. Length of time in the study was a median of 134 weeks (IQR: 89.0-179.0), in which a mean CIRS score change of 1.21 (SD 2.60) was observed. Being older (p< 0.001) and having a higher body mass index (p= 0.008) and diabetes (p= 0.014) were associated with an increased likelihood of worsening multimorbidity. PLWH with a higher level of multimorbidity at baseline were less likely to worsen over time (p< 0.001). As diabetes and weight predict worsening multimorbidity, routine diabetes screening, body mass index measurement, and multimorbidity status awareness are recommended.

Real-World Clinical Outcomes and Adverse Events in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib: A Single-Center Retrospective Study.

Background and Objectives: The treatment of chronic lymphocytic leukemia (CLL) has acquired new targeted therapies. In clinical trials, ibrutinib improved outcomes safely. Real-world data called for a reappraisal of ibrutinib strategies. We report on a single center's experience with ibrutinib monotherapy, aiming to explore the outcomes, tolerability, and prognosis of CLL patients in routine clinical practice. Materials and Methods: Data were collected from all CLL patients treated with ibrutinib at Fundeni Clinical Institute, Bucharest, Romania, between January 2016 and June 2021. Results: A total of one hundred twenty-three CLL adult patients were treated with ibrutinib. Of the patients, 87% had relapsed/refractory CLL. The median age at ibrutinib initiation was 65 years; 44.7% of patients were staged Rai III/IV. At 32-month median follow-up, the median progression-free survival (PFS) was 50 months, the overall survival (OS) was not reached, and the overall response rate (ORR) was 86.2%. The age or number of previous therapies did not impact outcomes or tolerability. An Eastern Cooperative Oncology Group performance status (ECOG PS) score ≥ 2 and shorter time from initiation of last therapy (TILT) before ibrutinib predicted inferior PFS. Baseline characteristics had no impact on the OS except for TILT in R/R CLL patients. Drug-related adverse events (AEs) of any grade and grade ≥ 3 AEs were reported in 82.1% and 30.9% of the patients, respectively. Infections were the most common AEs (29.3%). Drug discontinuation was permanent in 43.9% of patients, mainly due to disease progression (17.1%) and toxicity (8.9%). Patients with a Cumulative Illness Rating Scale (CIRS) score ≥ 6 had a higher risk for toxicity-related discontinuation. An ECOG PS ≥ 2 predicted an increased rate of permanent discontinuation and grade ≥ 3 AEs. Conclusions: The outcomes of this study align with the results from ibrutinib clinical trials. Our study demonstrated that poor patient fitness, early relapse before ibrutinib, and permanent ibrutinib discontinuation are essential outcome determinants. Patient comorbidity burden and fitness were significant predictors for ibrutinib intolerance.

Residual Disease Kinetics Among Patients with High-Risk Factors Treated with First-Line Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O): The Glow Study

Background: In the GLOW study (NCT03462719), fixed-duration Ibr+Ven demonstrated superior progression-free survival (PFS), deeper, better sustained undetectable minimal residual disease (uMRD) responses, and fewer patients (pts) requiring subsequent anti-cancer treatment versus Clb+O in older and/or comorbid pts with previously untreated chronic lymphocytic leukemia (CLL; Kater AP, et al. NEJM Evidence. 2022). Unmutated IGHV (uIGHV) and TP53 mutations are risk factors associated with worse outcomes for both chemoimmunotherapy and venetoclax plus anti-CD20 therapies for CLL. Here we investigate MRD kinetics and outcomes of Ibr+Ven in GLOW according to these risk factors. Methods: Pts aged ≥ 65 years or 18 to 64 years with cumulative illness rating scale score > 6 or creatinine clearance < 70 mL/min were enrolled and randomized 1:1 to Ibr+Ven (3 cycles of Ibr lead-in, followed by 12 cycles of Ibr+Ven) or 6 cycles of Clb+O, with a cycle defined as 28 days. Pts with del(17p) or known TP53 mutations at screening were excluded, and central evaluation of TP53 mutational status was performed during the study. The primary end point was PFS by independent review committee. Among pts with partial response or better, MRD in peripheral blood was evaluated using next-generation sequencing via clonoSEQ on-treatment and at 3-6 month intervals post-treatment. uMRD results are reported in peripheral blood (PB) at < 10-4 unless otherwise noted. Since the primary analysis, a post hoc retrospective reclassification of the IGHV status of baseline samples was conducted to reduce the number of unknowns. We used clonoSEQ data as part of CLL clonal testing (Adaptive Biotechnologies, Seattle, WA). Results: There were 106 pts randomized to Ibr+Ven and 105 to Clb+O. In the Ibr+Ven arm, uMRD rates increased from 46.2% after 6 cycles of the combination to 54.7% at 3 months after end of treatment (EOT+3), demonstrating that the majority of disease clearance in the PB occurred early, during the first 6 months of combination treatment. Post-treatment, 77.6% (45/58) of pts in the Ibr+Ven arm sustained their uMRD status from EOT+3 to EOT+18, compared with 12.2% (5/41) in the Clb+O arm. In the Ibr+Ven arm, 17/24 patients with intermediate MRD ≥ 10-4 to < 10-2 at EOT+3 did not worsen through EOT+18. Among pts with detectable MRD (≥ 10-4) at EOT+3, 6.5% (2/31) clinically progressed by EOT+18 in the Ibr+Ven arm versus 68.1% (32/47) in the Clb+O arm. After reclassification of baseline samples, uIGHV / mutated IGHV (mIGHV) / unknown status was 63.2%/30.2%/6.6% in the Ibr+Ven arm and 54.3%/33.3%/12.4% in the Clb+O arm. In the Ibr+Ven arm, rates of uMRD after 6 cycles of combination treatment and at EOT+3, respectively, were 52.2% and 59.7% in pts with uIGHV and 31.3% and 40.6% in pts with mIGHV (Fig A). On-treatment MRD kinetics differed by IGHV status in the Ibr+Ven arm, with uMRD achieved at a higher rate and earlier in pts with uIGHV. In the Ibr+Ven arm, uMRD was sustained post-treatment (from EOT+3 and EOT+18) in 80.0% (32/40) of pts with uIGHV and 76.9% (10/13) of pts with mIGHV. Among pts with detectable MRD (≥ 10-4) at EOT+3, 2/16 with uIGHV and 0/14 with mIGHV had clinically progressed by EOT+18 in the Ibr+Ven arm; corresponding rates were 83.3% (25/30) and 42.9% (6/14) in the Clb+O arm. Five of 7 pts with TP53-mutated CLL achieved uMRD at EOT+3 in the Ibr+Ven arm; TP53 variant allele frequencies ranged between 5.9% and 29.6% for these 5 pts and all maintained uMRD through EOT+18. With a median study follow-up of 34.1 months, PFS rates after IGHV reclassification were well sustained post-treatment regardless of IGHV status in the Ibr+Ven arm, while uIGHV pts in the Clb+O arm relapsed more quickly (Fig B). PFS, overall survival, and subgroup analyses with longer study follow-up will be presented. Conclusion: All-oral, once-daily, fixed-duration Ibr+Ven achieved uMRD responses that were better sustained than Clb+O during the first 18 months post-treatment. Notably, with Ibr+Ven, uMRD rates were higher and achieved earlier in pts with uIGHV CLL versus mIGHV CLL, while uMRD was similarly sustained post-treatment irrespective of IGHV status. Clinical progressions in the first 18 months post-treatment with Ibr+Ven were uncommon even among pts with detectable MRD ≥ 10-4. MRD kinetics and sustained responses demonstrate strong efficacy of the fixed-duration Ibr+Ven combination in older pts with high-risk genomic features. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MPN-076 Impact of Comorbidities and Response to Treatment on the MPN SAF Assessment of Philadelphia Chromosome-Negative Myeloproliferative Syndromes.

Philadelphia chromosome-negative myelopro-liferative neoplasms (MPN) are a heterogeneous group of hematological malignancies including essential thrombocythemia (ET), polycythemia (PV), and primary myelofibrosis (PMF). The MPN Symptom Assessment Form (SAF), or MPN 10, questionnaire is a validated tool for assessing the symptoms presented by patients with MPN and their evolution during treatment. To assess the impact of comorbidities and response to treatment on the symptomatology of patients with MPN assessed by the MPN SAF. This study, carried out in our hematology department, involved patients monitored and treated for MPN. We used the MPN SAF questionnaire, which includes 10 items rated from 0 to 10 in relation to the MPN symptom burden. Comorbidities were assessed using the Cumulative Illness Rating Scale (CIRS). Statistically, ANOVA and log rank tests were used to study the impact of comorbidities and response to treatment on MPN SAF scores. The tests are significant if P<0.05. Sixty-seven patients participated in this study, 31 women and 36 men, with a median age of 65 years [22-86]. Thirty-six (54%) patients had PV, 25 (37%) had ET, and 6 (9%) had PMF. Sixteen (24%) patients had splenomegaly, and half of these cases were bulky. The mean MPN SAF score was higher for patients with PMF (47) than for those with ET (26) or PV (21) (P=0.04). Forty-three (64%) patients had at least one associated disease, and 17 (25%) of these had a CIRS score ≥6. The MPN SAF scores were well correlated with the patients' comorbidity scores (P<0.001): patients with CIRS scores <6 had a mean MPN score of 48 versus 18 for patients with CIRS scores ≥6. Depending on the response to treatment and disease control, the MPN SAF scores were higher for patients refractory to treatment (mean: 35) than for those with complete or partial remission (17 and 22, respectively, P=0.02). Our study concludes that worsening of MPN symptoms is associated with comorbidities. It is very likely that associated diseases maintain a chronic inflammatory state that adds to that of chronic myeloid neoplasia, mainly when it is refractory to treatment.

Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities

BackgroundGLOW is a phase 3 trial evaluating the efficacy and safety of ibrutinib-venetoclax in older patients and/or those with comorbidities with previously untreated chronic lymphocytic leukemia (CLL).MethodsWe randomly assigned (1:1) patients 65 years of age or older or those 18 to 64 years of age who also had a Cumulative Illness Rating Scale (CIRS) score greater than 6 (CIRS scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or creatinine clearance of less than 70 ml/min, to ibrutinib-venetoclax (3 cycles ibrutinib lead-in, then 12 cycles ibrutinib-venetoclax) or chlorambucil-obinutuzumab (6 cycles). The primary end point was progression-free survival (PFS) assessed by an independent review committee. Secondary end points included undetectable minimal residual disease (uMRD), response rates, and safety.ResultsThis study enrolled 211 patients, with 106 randomly assigned to ibrutinib-venetoclax and 105 to chlorambucil-obinutuzumab. With a median follow-up of 27.7 months, there were 22 PFS events for ibrutinib-venetoclax and 67 events for chlorambucil-obinutuzumab. PFS was significantly longer for ibrutinib-venetoclax than for chlorambucil-obinutuzumab (hazard ratio, 0.216; 95% confidence interval [CI], 0.131 to 0.357; P<0.001). The improvement in PFS with ibrutinib-venetoclax was consistent across predefined subgroups, including patients 65 years of age or older or with a CIRS score greater than 6. The best uMRD rate in bone marrow by next-generation sequencing was significantly higher for ibrutinib-venetoclax (55.7%) than for chlorambucil-obinutuzumab (21.0%; P<0.001). The proportion of patients with sustained uMRD in peripheral blood from 3 to 12 months after end of treatment was 84.5% for ibrutinib-venetoclax and 29.3% for chlorambucil-obinutuzumab. Four patients treated with ibrutinib-venetoclax required subsequent therapy compared with 27 patients receiving chlorambucil-obinutuzumab (hazard ratio, 0.143; 95% CI, 0.050 to 0.410). Adverse events grade 3 or greater occurred for 80 (75.5%) and 73 (69.5%) patients receiving ibrutinib-venetoclax and chlorambucil-obinutuzumab, respectively, with neutropenia being most common in both arms (37 [34.9%] and 52 [49.5%]). There were 11 (10.4%) and 12 (11.4%) all-cause deaths in the ibrutinib-venetoclax and chlorambucil-obinutuzumab arms, respectively.ConclusionsIbrutinib-venetoclax, an all-oral, once-daily, fixed-duration combination, demonstrated superior PFS and deeper and better sustained responses versus chlorambucil-obinutuzumab as first-line CLL treatment in older patients and/or those with comorbidities. (Funded by Janssen Research & Development, LLC, and Pharmacyclics; ClinicalTrials.gov number, NCT03462719.)

First Prospective Data on Minimal Residual Disease (MRD) Outcomes after Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O) for First-Line Treatment of CLL in Elderly or Unfit Patients: The Glow Study

First Prospective Data on Minimal Residual Disease (MRD) Outcomes after Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O) for First-Line Treatment of CLL in Elderly or Unfit Patients: The Glow Study

Safety and Efficacy of Obinutuzumab Plus Fludarabine and Cyclophosphamide in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the GREEN Study

Safety and Efficacy of Obinutuzumab Plus Fludarabine and Cyclophosphamide in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the GREEN Study

Risk Factors of Readmissions in Geriatric Rehabilitation Patients: RESORT

ObjectiveTo evaluate the risk factors associated with 30- and 90-day hospital readmissions in geriatric rehabilitation inpatients. DesignObservational, prospective longitudinal inception cohort. SettingTertiary hospital in Victoria, Australia. ParticipantsGeriatric rehabilitation inpatients of the REStORing Health of Acutely Unwell AdulTs (RESORT) cohort evalutated by a comprehensive geriatric assessment including potential readmission risk factors (ie, demographic, social support, lifestyle, functional performance, quality of life, morbidity, length of stay in an acute ward). Of 693 inpatients, 11 died during geriatric rehabilitation. The mean age of the remaining 682 inpatients was 82.2±7.8 years, and 56.7% were women. InterventionsNot applicable. Main Outcome MeasuresThirty- and 90-day readmissions after discharge from geriatric inpatient rehabilitation. ResultsThe 30- and 90-day unplanned all-cause readmission rates were 11.6% and 25.2%, respectively. Risk factors for 30- and 90-day readmissions were as follows: did not receive tertiary education, lower quality of life, higher Charlson Comorbidity Index and Cumulative Illness Rating Scale (CIRS) scores, and a higher number of medications used in the univariable models. Formal care was associated with increased risk for 90-day readmissions. In multivariable models, CIRS score was a significant risk factor for 30-day readmissions, whereas high fear of falling and CIRS score were significant risk factors for 90-day readmissions. ConclusionsHigh fear of falling and CIRS score were independent risk factors for readmission in geriatric rehabilitation inpatients. These variables should be included in hospital readmission risk prediction model developments for geriatric rehabilitation inpatients.

Comorbidities Predict Inferior Survival in Patients Receiving Chimeric Antigen Receptor T Cell Therapy for Diffuse Large B Cell Lymphoma: A Multicenter Analysis

Chimeric antigen receptor T cell (CAR-T) therapy is approved for treatment of relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). Here we evaluate whether comorbidities, calculated using the Cumulative Illness Rating Scale (CIRS), predict survival for these patients. A retrospective chart review was performed at 4 academic institutions. All patients who underwent leukapheresis for commercial CAR-T therapy for R/R DLBCL were included. CIRS scores were calculated at the time of leukapheresis. High comorbidity was defined as either CIRS ≥7 or the presence of severe impairment (CIRS 3/4 in ≥1 system; CIRS-3+). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and differences in curves were detected by the log-rank test. A total of 130 patients were analyzed, 56.9% with CIRS ≥7 and 56.2% with CIRS-3+. After a median follow-up of 13 months, the median PFS was 6.7 months, and the median OS was not reached. On univariable analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.03-2.05; P=.03) and OS (HR, 1.76; 95% CI, 1.17-2.64; P=.007). Higher CIRS (CIRS ≥7 or CIRS-3+) was associated with inferior OS (HR, 2.12; 95%, CI, 1.06-4.22; P=.03) and a nonsignificant trend in worse PFS (HR, 1.45; 95% CI, .87-2.44; P=.16). In multivariable analyses, CIRS ≥7 or CIRS-3+ and ECOG PS maintained independent prognostic significance. Comorbidities as determined by CIRS and ECOG PS predict inferior survival in patients receiving CAR-T therapy for R/R DLBCL.

Fecal impaction is associated with postoperative urinary retention after hip fracture surgery.

Postoperative urinary retention (POUR) is a common hip fracture (HF) complication. Although fecal impaction (FI) is one of the oft-cited causes of POUR in clinical practice, evidence regarding this association is scarce. The aim of this study was to determine whether FI was associated with POUR after HF surgery in older patients. All patients consecutively admitted after a HF surgery in a geriatric perioperative unit were included in this cross-sectional study. FI was systematically assessed by a digital rectal exam at admission and according to clinical suspicion during the hospital stay. The dependent variable was POUR, systematically screened according to the department protocol and defined as a bladder volume>400ml requiring catheterization. The association between FI and POUR was assessed by multivariable analysis. A total of 256 patients were included (mean [SD] age 86 [6] years), (76% women): 108 (42%) presented FI and 63 (25%) POUR. The frequency of FI was higher with than without POUR (73% vs. 32%, P<0.001). On multivariable analysis, after adjusting for age, sex, Cumulative Illness Rating Scale score and anticholinergic load, FI was the only factor independently associated with POUR (odds ratio 4.78) [95% confidence interval 2.44-9.71], P<0.001. FI was the only independent factor associated with POUR after HF surgery in older adults. Further studies are needed to optimize perioperative geriatric care including FI and POUR assessment and management.

Efficacy and Safety of Front-Line Venetoclax and Rituximab (VenR) for the Treatment of Young Patients with Chronic Lymphocytic Leukemia and an Unfavorable Biologic Profile. Preliminary Results of the Gimema Study ‘Veritas‘

Efficacy and Safety of Front-Line Venetoclax and Rituximab (VenR) for the Treatment of Young Patients with Chronic Lymphocytic Leukemia and an Unfavorable Biologic Profile. Preliminary Results of the Gimema Study ‘Veritas‘