Cost of Disease Progression after Frontline (1L) R-CHOP in Diffuse Large B-Cell Lymphoma (DLBCL)

Introduction: While the chemoimmunotherapy combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is the standard-of-care in 1L treatment for DLBCL, 30-40% of patients either relapse or are refractory to R-CHOP (Coiffier et al. N Engl J Med 2002). The initiation of subsequent therapies post relapse is integral to relapsed/refractory (R/R) DLBCL management and is associated with substantial treatment cost. Previous studies of treatment costs for R/R DLBCL patients are outdated and exclude novel therapies (e.g. chimeric antigen receptor [CAR-]T therapies). Thus, the cost of disease progression may be underestimated. Using data through 2020, we sought to understand the economic burden associated with disease progression in the DLBCL treatment landscape. Methods: This was a retrospective cohort study using administrative claims data from IQVIA PharMetrics ® Plus (a US commercial claims database). We identified patients ≥18 years, who received 1L R-CHOP treatments between January 1, 2010 and June 30, 2018. Patients were required to have ≥1 inpatient claim or ≥2 outpatient claims with a DLBCL diagnosis from 1 year before to 90 days after initiating R-CHOP. End of therapy was defined as a gap of ≥60 days in the treatment regimen or initiation of new agents (OPTUM 2018). Using this definition as a proxy for progression, patients not receiving second-line (2L) treatment for ≥2 years were assigned to the 'no progression' cohort and those who initiated non-R-CHOP therapy after 1L therapy to the 'progression' cohort. In both cohorts, index date was defined as either 60 days after the end of 1L treatment, or the initiation of 2L treatment, whichever occurred first. All patients had continuous enrollment in medical and pharmacy benefits between R-CHOP initiation and ≥2 years post index date, allowing time for post-1L relapse. Costs per-patient-per-month (PPPM) and 3-year cumulative all-cause costs (2020 USD) were compared between cohorts. Generalized linear models (gamma distribution with log link) were performed to adjust for baseline characteristics, including age and payer type at index, sex, US region, Charlson Comorbidity Index (CCI), and baseline total cost of care 1 year before index date. Results: Overall, 871 patients were identified; 58% were female. The mean (standard deviation [SD]) age and CCI (excluding malignancy) at index date were 58.0 (11.7) years, and 2.5 (3.1) years, respectively. The mean follow-up period was 45 months. Patients in the 'no progression' cohort (N = 725; 83.2%) had similar baseline characteristics to those in the 'progression' cohort (N = 146; 16.8%). About half (N = 76; 52.1%) of the progression cohort had multiple relapse events, with 30.8% receiving ≥4 lines of therapy. Among the progression cohort, 73 (50.0%) and 10 (6.8%) patients received stem-cell transplant (SCT) and CAR-T therapy, respectively. The mean PPPM cost was higher among progressors than non-progressors (unadjusted: $10,163 vs $1,569; adjusted: $10,554 vs $1,561, p < 0.001, Table 1). The major cost driver for disease progression was inpatient costs (41.7% of total costs for progressors vs 19.1% for non-progressors). Cost of progression associated with multiple relapse events was more than twice the cost associated with a single event (unadjusted: $13,934 vs $6,069; adjusted: $14,676 vs $6,216, p < 0.001, Table 1). Compared with no progression, receiving novel treatments after 1L was associated with considerably higher costs (unadjusted: $14,539 [SCT] and $25,032 [CAR-T] vs $1,569; adjusted: $14,306 [SCT/CAR-T] vs $1,549, p < 0.001, Table 2). Similar trends were seen comparing unadjusted 3-year cumulative costs based on month of disease progression in patients in the 'no progression', 'progression' and SCT/CAR-T subgroups (Figure 1). Conclusion: In this analysis of insurance claims through 2020, we systematically selected patients who survived for at least 2 years after the index date; this represented approximately 80% of DLBCL patients treated with 1L R-CHOP. The cost of disease progression in DLBCL is considerable, especially among patients receiving novel treatments as later lines of therapy. The costs for patients experiencing multiple relapse events were more than twice the cost for patients with a single relapse event. Effective frontline treatments for DLBCL are needed to reduce the economic burden associated with disease progression. Figure 1 Figure 1. Disclosures Wang: Aurinia Pharmaceuticals Inc.: Current equity holder in publicly-traded company; Novavax, Inc.: Current equity holder in publicly-traded company; Oragenics, Inc.: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; The SPHERE Institute: Ended employment in the past 24 months; Genentech, Inc.: Current Employment; TG Therapeutics, Inc.: Current equity holder in publicly-traded company. Roth: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; Seattle Genetics: Consultancy; Bayer Healthcare: Consultancy; Bristol-Myers Squibb: Consultancy; Epigenomics AG: Consultancy. Ng: Genentech, Inc./F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company; Emory University, Rollins School of Public Health: Ended employment in the past 24 months. Hossain: Genentech, Inc.: Current Employment; Legend Biotech: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Li: F. Hoffmann-La Roche Ltd/Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Masaquel: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

The clinical efficacy of azathioprine as maintenance treatment for autoimmune pancreatitis: a systematic review and meta-analysis

The effectiveness of azathioprine (AZA) in preventing relapse and maintaining autoimmune pancreatitis (AIP) remission has been reported; however, most of these studies are case series with no randomized control trials available in the literature. Therefore, this study performed a systematic review and meta-analysis of the existing literature on this subject to determine the clinical efficacy of AZA as maintenance therapy for AIP patients. A systematic search was performed to identify studies on the clinical efficacy of AZA as maintenance therapy in AIP patients. The crude multiple relapse rate was estimated to assess the ability of AZA to control relapses in AIP. Pooled estimates were obtained using a random-effects model with the DerSimonian-Laird method. We identified AIP patients who did not respond to initial steroid treatment, experienced steroid weaning failure, or those who relapsed during remission as refractory cases. After reviewing the studies, ten articles fulfilled the inclusion criteria and were selected for meta-analysis. Of all 4504 patients, 3534 patients were treated with steroids, and 346 patients were treated with AZA for relapsed AIP. In this meta-analysis, 14/73 (19.2%) patients receiving AZA for refractory AIP relapsed. Meanwhile, 14/47 (29.8%) patients without AZA experienced relapse. The integrated odds ratio for relapse risk in patients receiving AZA was estimated to be 0.52 (p = 0.15). This systematic review and meta-analysis demonstrated the efficacy of AZA in preventing relapse of AIP, which supports the use of AZA as a maintenance treatment in patients with AIP who relapse upon withdrawal of steroid therapy.

The predictive power of expressed emotion and its components in relapse of schizophrenia: a meta-analysis and meta-regression

BackgroundSchizophrenia is a longstanding condition and most patients experience multiple relapse in the course of the condition. High expressed emotion (HEE) has been found to be a predictor of relapse. This meta-analysis and meta-regression examined the association of global EE and relapse specifically focusing on timing of relapse and EE domains.MethodsRandom-effects model was used to pool the effect estimates. Multiple random-effects meta-regression was used to compute the moderator analysis. Putative effect moderators including culture, EE measurements, age, length of condition and study quality were included.ResultsThirty-three prospective cohort studies comprising 2284 patients were included in the descriptive review and 30 studies were included for meta-analysis and meta-regression. Findings revealed that global HEE significantly predicted more on early relapse (⩽12 months) [OR 4.87 (95% CI 3.22–7.36)] than that on late relapse (>12 months) [OR 2.13 (95% CI 1.36–3.35)]. Higher level of critical comments (CC) significantly predicted relapse [OR 2.22 (95% CI 1.16–4.26)], whereas higher level of warmth significantly protected patients from relapse [OR 0.35 (95% CI 0.15–0.85)]. None of the moderators included significantly change the results.ConclusionsThese findings indicate that there is a dynamic interaction between EE-relapse association with time, and CC and warmth are the two important EE domains to influence relapse among patients with schizophrenia. Results also confirmed the foci of family interventions on reducing CC and improving warmth in relationship.

Pharmacotherapy of Central Serous Chorioretinopathy: A Review of the Current Treatments

Background: Central serous chorioretinopathy (CSC) is the fourth most frequent retinal disorder in terms of prevalence. It typically occurs in young subjects and affects men more often than women. CSC is characterized by serous retinal detachment (SRD) involving mainly the macular area. The clinical course is usually selflimited, with spontaneous resolution within 3 months. The persistence of SRD or multiple relapse may result in a chronic form of CSC distinguished by permanent retinal pigment epithelium (RPE) and photoreceptor damage. As the pathogenetic mechanism of CSC primarily involves RPE and choroidal vascularization, the current therapeutic approaches aim to restore the normal functions of RPE and normal choroidal vascular permeability. In this review, the authors aim to summarize the current therapeutic approach to CSC. Methods: A comprehensive review of the literature was conducted in PubMed by searching for relevant studies on the current therapeutic options for CSC, including simple observation, conventional laser treatment, subthreshold laser treatment (SLT), photodynamic therapy (PDT) with verteporfin, treatment with mineralocorticoid receptor (MR) antagonists and treatment with anti-vascular endothelial growth factor drugs. Results: Since most cases resolve spontaneously, the most common initial CSC treatment is observation. Current evidence suggests that PDT and SLT are valuable in improving visual acuity, reducing subretinal fluid and maintaining long-term effectiveness. No clear evidence of efficacy has been achieved for anti-VEGF. MR antagonists might be a viable choice for the treatment of chronic CSC. Conclusion: The pathophysiology of CSC remains poorly understood and as a consequence, the gold standard of care for CSC is yet to be defined. To date, PDT and SLT continue to offer good clinical outcomes. Positive preliminary results seem to emerge from the studies of MR antagonists.

P110α-mediated constitutive PI3K signaling limits the efficacy of p110δ-selective inhibition in mantle cell lymphoma, particularly with multiple relapse

Key Points The increased expression of PI3K p110α in mantle cell lymphoma, particularly at relapse, suggests a role for p110α in disease progression. A high PIK3CA/PIK3CD ratio identifies patients unlikely to respond to p110δ inhibitors and supports use of dual p110α/p110δ inhibitors in MCL.

Dose Intensity of Chemotherapy in Patients With Relapsed Hodgkin's Lymphoma

Purpose High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkin's lymphoma (HL). The intensity of treatment needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy. Patients and Methods Patients with histologically confirmed, relapsed HL were treated with two cycles of dexamethasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points. Results From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P < .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P < .001). Conclusion Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL.

Mutation of Cellular Retinoic Acid-Binding Protein-II (Crabp-II) Does Not Account for Resistance to All-Trans Retinoic Acid (ATRA) in Relapse Acute Promyelocytic Leukemia (APL).

An increase in CRABP-II has frequently been invoked as a cause of resistance to ATRA in APL due to cytoplasmic sequestration and catabolism of ATRA. However, recent evidence indicates that CRABP-II has a positive rather than a negative role in ATRA activity by facilitating delivery of ATRA to retinoic acid receptor-alpha (RARα) associated with ATRA target genes in the cell nucleus or/and by serving as a co-activator of RARα-regulated transcription. This implies that if CRABP-II has a role in the development of ATRA resistance in APL, this would more likely occur through a deficiency rather than from an increase in CRABP-II. We previously reported that CRABP-II is constitutively expressed at similar levels in pretreatment and relapse APL cells (Zhou, et al, Cancer Res58, 5770, 1998), suggesting that putative CRABP-II deficiency is not due to the loss of CRABP-II expression. To investigate the alternative possibility that CRABP-II deficiency might arise through inactivating mutations, we sequenced the entire coding region of CRABP-II from 18 cases of APL who had relapsed from prior ATRA-containing treatment regimens. In 8 cases RNA was transcribed by reverse transcriptase to cDNA and amplified by polymerase chain reaction (PCR), using primers anchored in the 5′ and 3′ untranslated region of mRNA; in 10 cases, genomic DNA was PCR amplified for sequence analysis, using primers anchored in the introns between the 4 exons of the gene. No CRABP-II mutations were identified. The samples tested included 11 first-relapse cases, 2 of whom were refractory to reinduction therapy with intravenous liposomal-ATRA, and 7 multiple relapse cases, all of whom were clinically refractory to ATRA and had, additionally, relapsed from arsenic trioxide therapy. Also, no mutations were found in 3 APL patients who had relapsed from chemotherapy-induced remissions or in 3 APL cell lines (NB4, UF-1 and AP-1060). Two heterozygous base substitutions were incidentally identified in CRABP-II intron 2 in a chemotherapy-only treated patient. These results indicate that CRABP-II mutations rarely, if ever, contribute to ATRA-resistance or disease relapse in APL.

Cologne High-Dose Sequential Chemotherapy in Relapsed and Refractory Hodgkin Lymphoma - Results of a Large Multicenter Study of the German Hodgkin Lymphoma Study Group (GHSG).

Purpose: Combination chemotherapy can cure patients (pts) with Hodgkin lymphoma (HD), but those with treatment failure or relapse still have a poor prognosis. We thus, designed a dose- and time-intensified high-dose sequential chemotherapy regimen with a final myeloablative course. Patients and Methods: Eligibility criteria included age 18–65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consists of two cycles DHAP (dexamethasone 40mg d1-4, high-dose cytarabin 2g/m2 12q d2, cisplatinum 100mg/m2 d1); pts with partial (PR) or complete remission (CR) received cyclophosphamide 4g/m2, followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8g/m2 plus vincristine 1,4mg/m2; and etoposide 2g/m2. The final myeloblative course was BEAM followed by PBSCT. Results: 102 pts (median age 34 years, range 18–64) were enrolled. The response rate (RR) at the final evaluation (100 days posttransplantation) was 80% (72% CR, 8% PR). PBSC harvest was succesful in 96% of pts. Toxicity was tolerable. With a median follow-up of 30 months (range 3–61 months) freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD: 41% and 48% and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after 2 cycles of DHAP (p &lt; 0.0001) and duration of first remission (PD and multiple relapse vs. early and late relapse; p = 0.0127) were prognostic factors for FF2F. Response after DHAP (p &lt; 0.0081), duration of first remission (p = 0.0017) and anemia (p = 0.019) were identified as prognostic factors for OS. Conclusion: We conclude that this regimen is feasible, tolerable and highly effective in poor risk patients with relapsed and refractory HD. Based on these results a prospective randomized european intergoup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol). First results of the second interim analysis of this study will be presented.