Healthcare resource utilization and costs during first salvage therapy for relapsed or refractory acute myeloid leukemia in the United States.

Real-world US healthcare resource utilization (HRU) and costs during first salvage therapy for relapsed/refractory (R/R) acute myeloid leukemia (AML) are described using IBM MarketScan® data (1/1/2007-6/30/2020). Treatments included high- (HIC) and low-intensity chemotherapy (LIC) alone, and gilteritinib, other FLT3 tyrosine kinase inhibitors (TKIs), and venetoclax with or without chemotherapy. Patients were diagnosed with R/R AML at ≥18 years of age between 1/1/2017-12/31/2019. Patient monthly all-cause HRU and costs were analyzed using a fixed-effects model. Data from 399 patients were analyzed (HIC, n = 104; LIC, n = 133; gilteritinib, n = 14; other FLT3 TKIs, n = 68; venetoclax, n = 80). Inpatient HRU was generally highest with HIC, whereas outpatient HRU was generally highest with LIC and venetoclax. Total all-cause incremental monthly costs appeared to be highest with HIC ($171,982) and similar for LIC ($60,512), gilteritinib ($47,218), other FLT3 TKIs ($43,218), and venetoclax ($77,566). Results highlight HRU and cost differences for R/R AML during first salvage therapy.

Assessment of Salvage Regimens Post-Chimeric Antigen Receptor T Cell Therapy for Patients with Diffuse Large B Cell Lymphoma.

Anti-CD19 chimeric antigen receptor T cell therapy (CAR19) represents a critical treatment modality for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, the majority of patients subsequently experience disease progression following CAR19, and data are limited on assessing the best salvage regimen for these patients. This study aimed to evaluate outcomes in R/R DLBCL patients with progressive disease post-CAR19 and to assess variables that predict response to salvage therapy. We performed a retrospective analysis of all patients with DLBCL who received CAR19 at our institution between January 2018 and February 2021, collecting data on demographic characteristics, disease characteristics, best response to CAR19, date of relapse or progression, and first salvage therapy and response to salvage. We analyzed patients according to whether they responded to CAR19 (responders) or did not (nonresponders). Salvage regimens were classified into 6 groups for analysis. Primary endpoints included overall survival (OS) and progression-free survival (PFS), calculated using the Kaplan-Meier method. Cox models were fit to evaluate the effect of prognostic factors. Among the 120 patients who received CAR19 during the analysis period were 69 responders who achieved a complete or partial response to CAR19 and 51 nonresponders, including 44 with stable or progressive disease and 7 who died before assessment. Thirty responders relapsed and 26 received salvage therapy, and 24 nonresponders received salvage therapy. The primary salvage regimens included lenalidomide-based regimens (n = 17; 34%), BTKi (n = 10; 20%), checkpoint inhibitor-based (n = 7; 14%), chemo-immunotherapy (n = 5; 10%), allogeneic hematopoietic stem cell transplantation (n = 5; 10%), and others (n = 6; 12%). There was no significant difference in OS based on salvage regimen (P = .4545). Responders who received salvage therapy had significantly longer OS than nonresponders (median OS not reached versus 10.9 months; P = .0187), and response to CAR19 and elevated lactate dehydrogenase level at time of salvage treatment were the only two statistically significant prognostic factors after accounting for other variables. Responders to CAR19 had significantly better outcomes with salvage therapy compared with nonresponders to CAR19. There was no significant difference in outcomes based on salvage regimen. Future research is needed to assess the best salvage regimen post-CAR19 failure.

Salvage surgery for recurrent carcinoma of the oral cavity: assessment of prognostic factors.

Salvage surgery is the most acceptable therapeutic option for disease control of loco-regional recurrences in oral cancers. Prognostic factors need to be assessed to select patients for salvage surgery who would benefit the most. This was a single-centre retrospective observational study conducted between 2015 and 2018. A total of 168 patients with recurrent oral cavity carcinoma who underwent salvage surgery were included for analysis. The primary endpoints of the study were to evaluate overall survival (rOS) after salvage surgery and prognostic factors affecting survival. In this study, the median rOS was 18 months and the median disease-free survival (rDFS) was 14 months. Advanced stage (hazard ratio (HR) 2.387, 95% confidence interval (CI) 1.496-3.808; P = 0.001) and multimodality treatment (HR 1.642, 95% CI 1.139-2.367; P = 0.008) in the initial disease, as well as nodal spread (HR 3.794, 95% CI 1.580-9.111; P = 0.008) and perineural invasion (HR 2.167, 95% CI 1.358-3.455; P = 0.001) in the recurrent disease, were found to adversely affect survival after salvage surgery. With thorough assessment of the prognostic factors and appropriate patient selection, survival may be favourable after salvage surgery for recurrent oral cavity carcinoma.

Economic burden in treated Japanese patients with relapsed/refractory large B-cell lymphoma.

Aim: To understand the economic burden of relapsed and refractory large B-cell lymphoma patients in Japan treated with salvage chemotherapy. Patients & methods: Patients who received systemic therapy after first-line treatment were analyzed to assess its associated cost and resource use using a retrospective claims database. The impact of COVID-19 was assessed separately. Results & conclusion: This study identified 2927 and 1085 patients in the second- (2L) and third-line (3L) cohorts. The median ages for the 2L and 3L cohorts were 71 and 70 years, respectively, with Charlson Comorbidity Score of 3. A majority of the patients had limited stem cell transplant due to advanced age. Median lengths of inpatient stay for the 2L and 3L cohorts were 118 and 116 days, respectively. The majority of costs were attributed to inpatient costs, and limited COVID-19 impact was observed in this study.

Patient-reported outcome and cost implication of acute salvage of infected implant-based breast reconstruction with negative pressure wound therapy with Instillation (NPWTi) compared to standard care.

INTRODUCTION: Implant loss due to infection is the most devastating complication of implant-based breast reconstruction. The use of negative pressure wound therapy with instillation(NPWTi) for salvage of infected implant-based breast reconstructions has shown promising results allowing early reinsertion of a new implant as an alternative to the current management with delayed reinsertion. This study compares the patient-reported outcome and cost implication of NPWTi to the current management. METHODS: Twenty cases of infected breast implants treated with NPWTi(V.A.C. VERAFLO™ Therapy), followed by early reinsertion of new implants were compared to 20 cases that had delayed reinsertion(non-NPWTi). Patient satisfaction was evaluated using the BREAST-Q questionnaire. The average cost per patient was calculated using total operative expense, cost of inpatient stay, investigations, antibiotics, and outpatient visits. RESULTS: Treatment with NPWTi allowed earlier reinsertion of a new implant (NPWTi: 10.3 ± 2.77days vs. non-NPWTi: 247.45±111.28days, p<0.001). Patients in the NPWTi group reported higher satisfaction. The average cost per patient for NPWTi and non-NPWTi was £14,343.13±£2,786.70 and £8,920.31±£3,005.73, respectively(p<0.001). All patients treated with NPWTi had one admission and spent 11.9 ± 4.1days as inpatients, while non-NPWTi patients had 2.1 ± 0.3 admissions(p<0.001) and spent 7.1 ± 5.8days(p<0.004) as inpatients. Patients treated with NPWTi had more procedures (NPWTi:3.35±0.81 Vs. non-NPWTi:2.2 ± 0.41, p = 0.006); however, three non-NPWTi cases required flap reconstruction. CONCLUSION: Patients treated with NPWTi reported higher satisfaction, received a new and earlier implant, and had fewer admissions and outpatient visits; however, they incurred higher average costs, longer inpatient stays, and underwent more procedures. Early implant reinsertion preserves skin envelope; hence avoiding additional cost and stress related to further major autologous reconstruction.

Quantifying the Effect of Topical Nitroglycerin on Random Pattern Flap Perfusion in a Rodent Model: An Application of the ViOptix Intra.Ox for Dynamic Flap Perfusion Assessment and Salvage.

BACKGROUND: Near-infrared spectroscopy can detect changes in tissue oxygenation postoperatively that predict flap necrosis. The authors hypothesized that this technology can be applied along with topical nitroglycerin to measure an improvement in tissue oxygenation that correlates with tissue salvage. METHODS: Dorsal, random pattern flaps measuring 10 × 3 cm were raised using Sprague-Dawley rats. Tissue oxygenation was measured after flap elevation in 10 locations using the ViOptix Intra.Ox. Animals were divided into three groups that received 30 mg of topical nitroglycerin daily, twice-daily, or not at all. Oxygenation measurements were repeated on postoperative day 1 and animals were euthanized on day 7 and evaluated for tissue necrosis. RESULTS: Tissue necrosis was greatest in controls (51.3 mm) compared to daily (28.8 mm) and twice-daily nitroglycerin (18.8 mm; p = 0.035). Three flap perfusion zones were identified: healthy (proximal, 50 mm), necrotic (distal, 20 mm), and watershed. Immediate postoperative tissue oxygenation was highest in healthy tissue (57.2 percent) and decreased to 33.0 and 19.3 percent in the watershed and necrotic zones, respectively (p < 0.001). One day after treatment with nitroglycerin, oxygenation in the healthy zone did not increase significantly (mean difference, -1.5 percent). The watershed (17.8 percent; p < 0.001) and necrotic zones (16.3 percent; p <0.001) did exhibit significant improvements that were greater than those measured in control tissues (7.9 percent; both p < 0.001). CONCLUSIONS: Serial perfusion assessment using the ViOptix Intra.Ox measured a significant improvement in flap oxygenation after treatment with topical nitroglycerin. Within the watershed area of the flap, this increase in tissue oxygenation was associated with the salvage of ischemic tissue.

Cytopathologic assessment of gloves and instruments after major head and neck surgery.

PURPOSE: To investigate the potential for cancer cells to be transferred between anatomic sites via instruments and other materials. MATERIALS AND METHODS: Pilot prospective study from April 2018-January 2019 at Rush University Medical Center. Glove and instrument washings were collected from 18 high-risk head and neck cancer resection cases (36 samples total). Each case maintained at least one of the following features in addition to a diagnosis of squamous cell carcinoma or sarcoma: palliative/salvage surgery, positive margins, extensive tumor burden, and/or extra capsular extension (ECE). Surgical gloves and four main instruments were placed through washings for blind cytological assessment (2 samples/case). RESULTS: 18 patients undergoing surgical tumor resection for biopsy-proven squamous cell carcinoma with at least one of the aforementioned characteristics were included. 26.7% of cases had ECE, 40.0% had positive final margins and 46.7% had close final margins. Tumor locations included: oral cavity (10), neck (4), parotid gland (2), and skin (2). Malignant cells were isolated on glove washings in 1 case (5.5%). No malignant cells were isolated from instrument washings. The single case of malignant cells on glove washings occurred in a recurrent, invasive squamous cell carcinoma of the scalp with intracranial extension. Anucleated squamous cells likely from surgeon skin were isolated from 94.4% of washings. Squamous cells were differentiated from mature cells by the absence of nuclei. CONCLUSIONS: Malignant squamous cells can be isolated from surgical glove washings, supporting the practice of changing of gloves after gross tumor resection during major head and neck cancer resections.

Early Assessment With Gastrointestinal Ultrasound in Patients Hospitalised for a Flare of Ulcerative Colitis and Predicting the Need for Salvage Therapy: A Pilot Study.

Approximately 30% of patients hospitalised with severe ulcerative colitis do not respond to corticosteroids, but the decision to introduce salvage therapy is delayed to at least the third day of treatment, according to the widely applied Oxford criteria to assess response. This pilot study aimed to determine if gastrointestinal ultrasound performed on admission can predict steroid-refractory disease. In 10 consecutive patients with severe ulcerative colitis, gastrointestinal ultrasound was performed within 24 h of admission. Six patients failed corticosteroids and required infliximab salvage therapy. Colonic bowel wall thickness was a median of 4.6 mm (range 4.2-5.6 mm) in those responding to steroids compared with 6.2 mm (6-7.9 mm) in those requiring salvage therapy (p = 0.009). Any colonic segment with a bowel wall thickness of >6 mm was associated with the need for salvage therapy (p = 0.033). Gastrointestinal ultrasound may provide an early indication of poor corticosteroid response and enable a timelier introduction of salvage therapy in patients with severe ulcerative colitis.

IAP Chemotherapy Regimen Is a Viable and Cost-effective Option in Children and Adolescents With Osteosarcoma: A Comparative Analysis With MAP Regimen on Toxicity and Survival.

BACKGROUND: Cisplatin and doxorubicin are integral components of chemotherapy regimens in the treatment of osteosarcoma. Choice of third agent high-dose methotrexate (HDMTX) or an alkylating agent such as ifosfamide is debatable. The present study compared the impact of MAP (HDMTX-doxorubicin-cisplatin) and IAP (ifosfamide-doxorubicin-cisplatin) chemotherapy regimens on toxicity and survival in children and adolescents with osteosarcoma. MATERIALS AND METHODS: This was a retrospective study including patients 18 years and younger with osteosarcoma during the study period. Clinical, demographic, chemotherapy regimen, and surgical details and treatment-related toxicity were retrieved from hospital medical records. Prognostic factors affecting overall survival (OS) and event-free survival (EFS) were analyzed. RESULTS: Among 102 patients included in the study, 59 (57.8%) and 43 (42.2%) patients were treated with MAP and IAP regimens, respectively. Two groups were comparable in terms of pretreatment characteristics and surgical treatment. Overall, 95.9% patients underwent limb salvage surgery. There was a statistically increased incidence in supportive care admissions and delay in starting the next cycle of chemotherapy in the MAP group. Among the MAP cohort, the 5-year OS and EFS were 62% and 55% compared with 47% and 44%, respectively, in the IAP cohort (P=0.143 and 0.316, respectively). On univariate and multivariate analyses, statistically significant factors affecting EFS of the whole group included tumor size, stage, site of metastasis, histologic necrosis, and type of surgery. CONCLUSIONS: OS and EFS with both regimens were similar. However, the MAP regimen was associated with a statistically significant increase in incidence of supportive care admissions, delay in next cycle of chemotherapy, and predicted higher cost of treatment.

Reconstruction After Salvage Total Laryngectomy: A Cost-effectiveness Analysis.

OBJECTIVE: To determine the most cost-effective reconstruction method after salvage total laryngectomy. STUDY DESIGN: Cost-effectiveness analysis. SETTING: Tertiary care hospitals with head and neck oncologic and reconstructive surgeons. SUBJECTS AND METHODS: We constructed a Markov-based decision model to compare reconstruction by primary closure to pectoralis flap and free flap after salvage total laryngectomy. The model simulated disease with transition probabilities and health utilities found in primary literature and estimated the average overall cost of each reconstructive method using Medicare billing codes. Effectiveness was compared using quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were performed to scrutinize the conclusions of our model. Reconstruction methods were compared using incremental cost-effectiveness ratios (ICERs). In the United States, less than $150,000 per QALY gained is considered cost-effective (2019 US dollars). RESULTS: Our base case analysis revealed that primary closure was less expensive ($44,370) and yielded more QALYs (0.91) than both pectoralis ($45,163, 0.81 QALYs) and free flap ($46,244, 0.85 QALYs), making it the most cost-effective option. Between flaps, free flap was cost-effective over pectoralis flap (ICER = $27,025/QALY gained). Sensitivity analyses showed primary closure as cost-effective 69% of the time over either flap. These conclusions were sensitive to the health utilities (quality of life) of each method of reconstruction. CONCLUSION: Tissue flaps to augment closure after salvage total laryngectomy are not always the most cost-effective reconstructive option. The long-term morbidity of flap surgery oftentimes outweighs the benefit of lowering fistula rates after surgery. Careful consideration must be taken when advising patients of their reconstructive options.

The principle of salvage in the context of COVID-19.

The prioritisation of scarce resources has a particular urgency within the context of the COVID-19 pandemic crisis. This paper sets out a hypothetical case of Patient X (who is a nurse) and Patient Y (who is a non-health care worker). They are both in need of a ventilator due to COVID-19 with the same clinical situation and expected outcomes. However, there is only one ventilator available. In addressing the question of who should get priority, the proposal is made that the answer may lie in how the pandemic is metaphorically described using military terms. If nursing is understood to take place at the 'frontline' in the 'battle' against COVID-19, a principle of military medical ethics-namely the principle of salvage-can offer guidance on how to prioritise access to a life-saving resource in such a situation. This principle of salvage purports a moral direction to return wounded soldiers back to duty on the battlefield. Applying this principle to the hypothetical case, this paper proposes that Patient X (who is a nurse) should get priority of access to the ventilator so that he/she can return to the 'frontline' in the fight against COVID-19.

Hypofractionated Postprostatectomy Radiation Therapy for Prostate Cancer to Reduce Toxicity and Improve Patient Convenience: A Phase 1/2 Trial.

PURPOSE: The phase 1 portion of this multicenter, phase 1/2 study of hypofractionated (HypoFx) prostate bed radiation therapy (RT) as salvage or adjuvant therapy aimed to identify the shortest dose-fractionation schedule with acceptable toxicity. The phase 2 portion aimed to assess the health-related quality of life (QoL) of using this HypoFx regimen. METHODS AND MATERIALS: Eligibility included standard adjuvant or salvage prostate bed RT indications. Patients were assigned to receive 1 of 3 daily RT schedules: 56.6 Gy in 20 Fx, 50.4 Gy in 15 Fx, or 42.6 Gy in 10 Fx. Regional nodal irradiation and androgen deprivation therapy were not allowed. Participants were followed for 2 years after treatment with outcome measures based on prostate-specific antigen levels, toxicity assessments (Common Terminology Criteria for Adverse Events, v4.0), QoL measures (the Expanded Prostate Cancer Index Composite [EPIC] and EuroQol EQ-5D instruments), and out-of-pocket costs. RESULTS: There were 32 evaluable participants, and median follow-up was 3.53 years. The shortest dose-fractionation schedule with acceptable toxicity was determined to be 42.6 Gy in 10 Fx, with most patients (23) treated with this schedule. Grade 3 genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 3 patients and 1 patient, respectively. There was 1 grade 4 sepsis event. Higher dose to the hottest 25% of the rectum was associated with increased risk of grade 2+ GI toxicity; no dosimetric factors were found to predict for GU toxicity. There was a significant decrease in the mean bowel, but not bladder, QoL score at 1 year compared with baseline. Prostate-specific antigen failure occurred in 34.3% of participants, using a definition of nadir plus 2 ng/mL. Metastases were more likely to occur in regional lymph nodes (5 of 7) than in bones (2 of 7). The mean out-of-pocket cost for patients during treatment was $223.90. CONCLUSIONS: We identified 42.6 Gy in 10 fractions as the shortest dose-fractionation schedule with acceptable toxicity in this phase 1/2 study. There was a higher than expected rate of grade 2 to 3 GU and GI toxicity and a decreased EPIC bowel QoL domain with this regimen. Future studies are needed to explore alternative adjuvant/salvage HypoFx RT schedules after radical prostatectomy.

Institutional financial toxicity of failure to adhere to treatment guidelines for head and neck squamous cell carcinoma.

BACKGROUND: Delays in treatment of head and neck squamous cell carcinoma (HNSCC) are known to increase disease recurrence, generating the need for additional salvage treatment, often with immunotherapy. METHODS: Three treatment metrics were identified: time from diagnosis to treatment initiation (TTI), time from surgery to postoperative radiotherapy (surg → PORT), and total treatment package time (TPT). Financial toxicity was calculated using hazard ratios, pembrolizumab cost, and dosing data for a Veterans Health Administration (VHA) institutional cohort (n = 338) and a standardized cohort (n = 100). RESULTS: Estimated financial toxicity for the VHA cohort was $2 047 407, $316 545, and $1 114 101 for TTI, surg → PORT, and TPT, respectively. Estimated financial toxicity for the standardized patient cohort was $454 028, $544 576, and $1 879 628 for TTI, surg → PORT, and TPT, respectively. CONCLUSIONS: Failure to meet established HNSCC treatment metrics generates significant, yet avoidable, institutional financial toxicity which is particularly relevant to integrated single-payer systems such as the VHA in the modern immunotherapy era.

Bispecific antibodies in acute lymphoblastic leukemia therapy.

INTRODUCTION: Blinatumomab, first in a class of bispecific T-cell engagers, revolutionized treatment paradigm of B-cell precursor relapsed/refractory or minimal residual disease positive acute lymphoblastic leukemia (ALL) in adults and children, inducing deep remissions in a proportion of patients. However, significant numbers of patients do not respond or eventually relapse. Strategies for improvement of treatment outcomes are required. AREAS COVERED: This review discusses the main structural and functional features of blinatumomab, and its place in the treatment of ALL. Furthermore, prospects to increase the efficacy of blinatumomab are addressed. The developments in the field of bispecific antibodies and their possible implications for treatment of ALL are reviewed. EXPERT OPINION: Better understanding the mechanisms of response and resistance to blinatumomab might help us to identify the group of patients benefiting most from treatment and to spare potentially toxic subsequent treatment strategies. Data emerging from ongoing clinical trials might change the treatment landscape of ALL and beyond. Early use of blinatumomab in frontline protocols with more advantageous treatment sequences and in combination with other targeted therapies might reduce the failure rates. Exponentially increasing number of novel treatment options and their possible combinations might complicate treatment decision-making without data from randomized trials.

Cost utility analysis of tisagenlecleucel vs salvage chemotherapy in the treatment of relapsed/refractory diffuse large B-cell lymphoma from Singapore's healthcare system perspective.

BACKGROUND: Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) have limited treatment options and poor prognoses. Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy has shown early promise in improving survival outcomes, but at a high upfront cost. This study evaluated the cost-effectiveness of tisagenlecleucel versus salvage chemotherapy for treating patients with r/r DLBCL who have failed at least 2 lines of systemic therapies. METHODS: A hybrid decision tree and three-state partitioned survival model (progression-free (PF), progressive disease and death) was developed from the Singapore healthcare payer perspective. Survival curves from JULIET trial and CORAL-1 extension study were extrapolated beyond trial period over a 15-year time horizon to estimate the underlying progression-free survival and overall survival parametric distributions for both arms. Health state utilities were retrieved from the literature, and direct costs were sourced from public healthcare institutions in Singapore. One-way probabilistic sensitivity analyses and scenario analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results. RESULTS: Compared with salvage chemotherapy, tisagenlecleucel was associated with a base-case incremental cost-effectiveness ratio (ICER) US$508,530 (S$686,516) per quality adjusted life year (QALY) gained and US$320,200 (S$432,269) per life year (LY) gained. One-way sensitivity analysis showed the ICER was most sensitive to time horizon, PF utility and cost of tisagenlecleucel. Scenario analyses confirmed that the ICERs remained high under favorable assumptions and substantial price reduction was required to reduce the ICER. CONCLUSIONS: Our analysis showed tisagenlecleucel use in r/r DLBCL patients who failed at least 2 prior lines of systemic therapies was associated with exceedingly high ICER, which is unlikely to represent good use of healthcare resources. Comparative clinical evidence from the ongoing trials might provide more insight into future evaluations.