Cost-Effectiveness Analysis of CAR T-Cell Therapies vs Antibody Drug Conjugates for Patients with Advanced Multiple Myeloma.

OBJECTIVES: Among advanced multiple myeloma (MM) patients, B-cell maturation antigen (BCMA) specific targets like Belantamab Mafodotin (belamaf) and CAR T-cell therapies have been shown to improve clinical outcomes, but at significant costs. To compare the expected costs per quality-adjusted life years (QALYs) gained among a hypothetical cohort of triple refractory MM patients treated with one of three BCMA-directed therapies: (1) idecabtagene vicleucel (ide-cel), (2) ciltacabtagene autoleucel (cilta-cel), and (3) belamaf for up to 20 months. METHODS: In this cost-effectiveness analysis, we built a Monte Carlo Markov Chain microsimulation model using estimates and parameters from the evidence on MM treatment for 10 000 hypothetical patients between the ages for 40 and 80. We assigned expected years of life remaining and made varying assumptions about survival beyond 5 years. RESULTS: We predicted total cost of treatment for CAR-T therapy to be six times greater than for belamaf, but the QALYs gained from treatment are 6 to 8 times greater. Ide-cel was weakly dominated by cilta-cel and our base-case incremental cost effectiveness ratio (ICER) comparing cilta-cel with belamaf was $109,497 per QALY gained, averaging $123,618 in probabilistic sensitivity analyses. CONCLUSIONS: These findings hinge on the assumption of longer-term survival but suggest that the use of CAR-T therapy is approaching standard ICER thresholds.

Post-relapse survival in Waldenstrom macroglobulinemia patients experiencing therapy failure following autologous transplantation.

Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative malignancy. Autologous hematopoietic cell transplantation (auto-HCT) is considered in a subset of WM patients with relapsed disease. While registry data has shown a benefit for auto-HCT in relapsed WM, there is a paucity of data on outcomes of patients relapsing after auto-HCT. Eligibility criteria included adult patients with relapsed/refractory WM who underwent auto-HCT between 2007 and 2017. The primary endpoint was post-relapse overall survival (PR-OS). Secondary endpoints were to identify factors prognostic of PR-OS. Of the 48 patients with WM who underwent auto-HCT, 22 (46%) experienced relapse following auto-HCT. Median PR-OS of relapsed WM patients after auto-HCT (n = 22) was not reached (NR) (95% confidence interval [CI]: 17.5 months-NR). Among patients who relapsed <1 year versus ≥1 year from auto-HCT, the median PR-OS was 18.4 months (95%CI: 0.8-NR) months and NR (95%CI: 17.5-NR), respectively (p = 0.06). Of note, disease status at the time of transplant, CR/VGPR versus partial remission did not appear to impact PR-OS. The median PR-OS was significantly longer in patients who received ibrutinib in the post-transplant setting compared to those who did not (NR vs. 18.4 months, 95%CI: 9.1-NR, p = 0.02). On univariable analysis, the presence of complex karyotype (RR = 4.87, 95% CI = 1.22-19.53) and a higher number of prior lines of therapy (RR = 1.81, 95% CI = 1.23-2.67) were associated with a significantly higher risk of relapse. This is the only study to date that evaluated outcomes of WM patients who relapsed following auto-HCT and provides a benchmark for future trials evaluating survival following auto-HCT relapse.

The impact of bridging therapy prior to CD19-directed chimeric antigen receptor T-cell therapy in patients with large B-cell lymphoma.

In the relapsed/refractory setting for treatment of large B-cell lymphoma (LBCL), chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR-T cells are manufactured. Patients (n = 75) undergoing CAR-T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high-dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome between BT and NBT (P = 0·18 and P = 0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P = 0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P = 0·04). Disease response at last follow-up, progression-free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR-T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR-T therapy.

Novel prognostic scoring system for autologous hematopoietic cell transplantation in multiple myeloma.

We studied 2,528 patients with upfront autologous haematopoietic cell transplantation (AHCT) for multiple myeloma (MM) from 2008-2017 to develop a prognostic model to predict outcomes. High-risk cytogenetics included t(4;14), t(14;16), t(14;20), del13q on karyotype, del17p, +1q or 1pdel. A Cox model identified factors prognostic of progression/relapse in a training subset (n = 1,246). A weighted score using these factors was assigned to a validation cohort (n = 774). Presence of high-risk cytogenetics [hazard ratio, (HR) 1·68 (1·3-2·17)] and pre-AHCT bone marrow plasma cells (BMPCs) ≥10% [1·68 (1·33-2·12)] were assigned 4 points each; albumin at diagnosis <3·5 g/dl [1·31 (1·07-1·61)] 2; standard risk cytogenetics 1, and no cytogenetics abnormality, BMPCs <10% at AHCT and albumin ≥3·5 g/dl at diagnosis 0 points each. A three-category system with low risk (0-3), intermediate risk (4-8) and high risk (9-10) showed 3-year progression-free survival in the low vs. intermediate vs. high risk of 58% (95% CI: 52-63) vs. 49% (95% CI: 43-56) vs. 31% (95% CI: 12-51), P < 0.001 respectively, and 3-year OS in low vs. intermediate vs. high risk of 88% (95% CI: 84-91) vs. 81% (95% CI: 76-86) vs. 64% (95% CI: 39-80); P < 0·001. Our prognostic scoring system can identify MM patients at risk for early relapse after AHCT.

Hematopoietic Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Updated 2019 Evidence-Based Review from the American Society for Transplantation and Cellular Therapy.

The role of hematopoietic cell transplantation (HCT) in adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based on the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL, and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Axicabtagene ciloleucel (YESCARTA; Kite Pharma, a Gilead Company, Los Angeles CA) and tisagenlecleucel (KYMRIAH; Novartis Pharmaceuticals Corp., Basel, Switzerland) are two CD19-directed chimeric antigen receptor (CAR) T cell products currently approved by the US Food and Drug Administration; the European Medicines Agency; Health Canada; Ministry of Health, Labor and Welfare (Japan); and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL). Although this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate use of this novel therapy and of short- and long-term toxicities. To address these issues, representatives of the American Society of Transplantation and Cellular Therapy convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts. The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the use of CD19 CAR T cell products for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas.

Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Blood and Marrow Transplantation.

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

Analysis of Clinical Factors and Outcomes Associated with Nonuse of Collected Peripheral Blood Stem Cells for Autologous Stem Cell Transplants in Transplant-Eligible Patients with Multiple Myeloma.

Collection and storage of peripheral blood stem cells (PBSCs) for use in autologous stem cell transplantation (ASCT) upon first disease relapse is an accepted practice for eligible patients with multiple myeloma (MM). However, little is known about the factors and outcomes associated with nonuse of these collected and stored PBSCs by MM patients who intended to have a delayed ASCT. From January 1, 2004 to December 31, 2014 we identified 342 patients who underwent collection and storage of their PBSCs in anticipation of a delayed ASCT upon first disease relapse. Among these, 176 patients (11%) had not proceeded to a delayed ASCT at the time of this study analysis. The most common reason for not undergoing an ASCT was not experiencing a relapse on first-line therapy (53%, n = 94). However, 11% of patients (n = 37) who planned for a delayed ASCT were unable to undergo an ASCT at disease relapse. Comparison with a control group of MM patients who underwent an upfront ASCT suggested a worse overall survival from diagnosis in these patients who were ASCT ineligible at disease relapse (112 versus 80 months, P = .011). This study provides valuable data for patients and care providers to take into consideration when deciding on whether to pursue an upfront or a delayed ASCT.

Safety and Efficacy of Infliximab Therapy in the Setting of Steroid-Refractory Acute Graft-versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first-line treatment; however, less than one-half of patients achieve durable remission. Studies suggest that TNF-α, a cytokine released from the bone marrow during conditioning, is involved in the pathogenesis of aGVHD. We retrospectively evaluated the outcome of anti-TNF-α therapy with infliximab in 35 patients with steroid refractory (SR) aGVHD. Infliximab was administered intravenously at 10 mg/kg for a median of 4 doses (range, 1 to 6) on a weekly basis. The overall response rates were 40% (17% complete response [CR], 23% partial response [PR]) at 4 weeks, 23% (9% CR, 14% PR) at 8 weeks, and 17% (all CR) at 12 weeks. Twenty-nine (83%) patients had infectious complications within 12 weeks of initiation of infliximab. These infections included 40 bacterial infections, 6 invasive fungal infections, and 5 viral reactivations. Twelve patients (34%) died secondary to infections. Overall survival at 12 weeks and 6 months from the start of infliximab therapy was 37% (13 of 35) and 17% (6 of 35), respectively; with most deaths secondary to complications from GVHD and infections. In conclusion; the use of infliximab therapy in patients with SR-aGVHD is associated with a modest poorly sustained response along with a heightened risk of severe infections. Future studies with more effective and less toxic therapies are needed for these patients.

Predictors of the Use of Specific Critical Care Therapies in Patients With Metastatic Cancer.

OBJECTIVE: Understanding which factors are associated with the use of critical care therapies (CCTs) can help with clinical decision-making and goals of care discussion. The goal of this study was to describe the predictors of CCT use (eg, mechanical ventilation, tracheostomy, percutaneous endoscopic gastrostomy tube, total parenteral nutrition, acute use of dialysis) in hospitalized patients with metastatic cancer. METHODS: We used the 2010 California State Inpatient Databases sponsored by the Agency for Healthcare Research and Quality to identify all hospitalizations with a diagnosis of metastatic cancer (patients aged ≥18 years). We examined the predictors of any CCT use (and invasive mechanical ventilation [IMV] use), stratified by do-not-resuscitate (DNR) status, using multivariable logistic regression models. RESULTS: We identified 99,085 hospitalizations involving patients with metastatic cancer; 9.4% received any CCTs and 4.7% received IMV. Predictors of CCT use in the no-DNR group included principal diagnosis of infections (vs cancer-related), greater burden of comorbidities, and presence of weight loss. Predictors of CCT use in the DNR group were similar, but also included non-white races. Liver disease was also a predictor of IMV use in the no-DNR group. Patients with metastatic lung cancer (vs breast and genitourinary) with no DNR were more likely to receive CCT (and IMV). CONCLUSIONS: Higher burden of comorbidities, weight loss, liver disease, lung cancer subtype, and diagnosis of infections were associated with higher odds of receiving CCTs or IMV. These findings may help clinicians determine in whom to prioritize discussions around goals of care, especially in the group without a DNR status.

Predictors of In-Hospital Mortality in Patients With Metastatic Cancer Receiving Specific Critical Care Therapies.

BACKGROUND: In-hospital mortality is high for critically ill patients with metastatic cancer. To help patients, families, and clinicians make an informed decision about invasive medical treatments, we examined predictors of in-hospital mortality among patients with metastatic cancer who received critical care therapies (CCTs). PATIENTS AND METHODS: We used the 2010 California Healthcare Cost and Utilization Project: State Inpatient Databases to identify admissions of patients with metastatic cancer (age ≥18 years) who received CCTs, including invasive mechanical ventilation (IMV), tracheostomy, percutaneous endoscopic gastrostomy (PEG) tube, acute use of dialysis, and total parenteral nutrition (TPN). We first described the characteristics and outcomes of patients who received any CCTs. We then used multivariable logistic regression models with generalized estimating equations (to account for clustering within hospitals) to identify predictors of in-hospital mortality among patients who received any CCTs. RESULTS: For 2010, we identified 99,085 admissions among patients with metastatic cancer. Of these, 9,348 (9.4%) received any CCT during hospitalization; 50% received IMV, 15% PEG tube, 8% tracheostomy, 40% TPN, and 8% acute dialysis. Inpatient mortality was 30%. Of patients who received any CCT and survived to discharge, 27% were discharged to a skilled nursing facility. Compared with patients who died, costs of care were $3,019 higher for admissions in which patients survived the hospitalization. Predictors of in-hospital mortality included non-white race (vs whites), lack of insurance (vs Medicare), unscheduled admissions, principal diagnosis of infections (vs cancer-related), greater burden of comorbidities, end-stage renal disease, liver disease and lung cancer (vs other cancers). CONCLUSIONS: Although more studies are needed to better understand risks and benefits of specific treatments in the setting of specific cancer types, these data will help to inform decision-making for patients with metastatic cancer who become critically ill.

A rare case of acute respiratory distress syndrome secondary to acute lithium intoxication.

Lithium carbonate is a widely administered antimanic drug used for the treatment of bipolar disorder, schizoaffective disorder, and depression. Despite the established clinical efficacy of lithium, its usage must be approached with caution due to its narrow therapeutic index. Lithium poisoning results in multisystem toxicity, and characteristic clinical manifestations are directly correlated to serum lithium concentration. We describe a rather rare but fatal side effect of lithium: acute respiratory distress syndrome (ARDS) in a 46-year-old female on lithium for the treatment of bipolar disease. She was referred for generalized weakness, found in hemodynamic compromise, and had laboratory data significant for a lithium level of 3.3 mmole/L, needing emergent hemodialysis. Subsequently, she developed hypoxic respiratory failure requiring intubation. Her chest x-rays showed new bilateral pulmonary edema, the computed tomography scan showed extensive alveolar consolidation and V/Q scan of low probability for pulmonary embolism. She underwent 3 dialysis sessions and supportive care and was able to be extubated in 5 days. To our knowledge, 4 cases of ARDS after the onset of lithium toxicity have been documented. All patients presented with altered mental status at serum lithium levels ranging from 3.8 to 4.9 mmole/L and cardiogenic etiologies in addition to other likely causes of ARDS were ruled out in each case. The patients were treated with saline hydration (50%) or hemodialysis (50%), indicating that hemodialysis may be a permissive factor in lithium-associated ARDS development rather than a required component. Taken together, we believe that lithium is a likely culprit in the initiation of ARDS and propose the addition of ARDS to the family of clinical manifestations of severe lithium toxicity.

Prevalence of Race/Ethnicity Reporting in Light Chain (AL) Amyloidosis Clinical Research in the USA.

Little is known about racial differences in the incidence of light chain (AL) amyloidosis despite the well-documented racial disparities in the epidemiology of other plasma cell disorders. The goal of this study was to examine the extent to which published clinical research in AL amyloidosis report information on patients' race. Clinical research publications in AL amyloidosis between January 1, 2010, and December 31, 2020, from the USA were identified. In addition to the reporting of race, study design, funding, cohort size, year of publication, impact factor of publication journal, and first author degree were abstracted. Among papers reporting race, we also assessed whether ethnicity was reported separately. A PubMed search yielded 2,770 papers of which 220 met the pre-specified criteria for analysis. Of those, 37 (16.5%) reported race. Single institution publications, those with physicians as first authors, and those published in journals with impact factor 6 or higher were less likely to report race. On multivariate analysis, only single institution studies were negatively associated with race reporting. Of the 37 papers reporting race, none defined it in methods, 16% stated how race was identified, and 19% discussed its significance. Ethnicity was reported in 6 studies. Our results indicate that race/ethnicity is underreported in USA. AL amyloidosis clinical literature leads to a challenge for identifying potential racial/ethnic disparities. Standards for collecting and reporting racial/ethnic demographics are needed. Clear and consistent reporting of race and ethnicity of clinical populations is a necessary first step in identifying disparities and promoting equitable care.