Risk Factors for Cost-Related Delays to Medical Care Among Lymphoma Patients: A 22-Year Analysis of a Nationally Representative Sample.

BACKGROUND: An estimated 85,000 cases of lymphoma (Hodgkin and non-Hodgkin lymphoma) were diagnosed in the United States in 2020. Financial insecurity is known to negatively impact health outcomes. In 2021, as Americans continue to file for unemployment at rates far above pre-COVID-19 pandemic peak levels, there is a persistent need to address the economic burden of diagnoses and threat of financial stressors and its related conditions, which are already known to cause substantial economic burden. PATIENTS AND METHODS: Data were obtained from the National Health Interview Survey (NHIS), a cross-sectional survey conducted annually by the National Center for Health Statistics. Two questions were asked of patients to identify potential risk factors of financial insecurity regarding patients' ability to pay medical bills. NHIS respondents between the years 1997 and 2018 self-reporting a history of lymphoma diagnoses was included in the analysis. RESULTS: Among over 2 million respondents to the NHIS between 1997 and 2018, 1619 individuals reported a history of lymphoma; 9.95% reported delaying medical care due to cost within the previous 12 months; and 6.52% reported not being able to afford medical care in the previous 12 months. Among the subgroups that had the highest risk of delaying medical care were patients between the ages of 25 and 64 years and the uninsured. CONCLUSION: Financial burdens impede patients' abilities to access and adhere to care, which can contribute to poorer health outcomes. As financially insecure patients continue to present with lymphoma diagnoses, it is vital for practicing hematologists to understand the links among health care, financial insecurity, and demographic risk factors in order to devise and implement appropriate interventions.

Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIMSM.

BACKGROUND: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2). PATIENTS AND METHODS: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in ProleukinR Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIMSM) beginning in 2011. Statistical analyses were performed using datasets as of September 24, 2015. RESULTS: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2. CONCLUSIONS: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients.

Low serum vitamin D occurs commonly among multiple myeloma patients treated with bortezomib and/or thalidomide and is associated with severe neuropathy.

PURPOSE: Previous studies have shown that low serum vitamin D levels have been associated with many skeletal and non-skeletal disorders. We studied the relationship between 25-hydroxyvitamin D (25D) levels and motor and sensory peripheral neuropathy (PN) among multiple myeloma (MM) patients who have been treated with bortezomib and/or thalidomide. METHODS: We performed a study of 111 MM patients who had received at least one of these two agents for at least 12 weeks by correlating physical exam/neurologic assessment findings with patient self-assessment responses. RESULTS: The median age of study patients was 66 years (range 42-89 years) and 54 % were males. 25D levels were determined, and complete history and physical and neurologic examinations were performed at the same study visit. In addition, study subjects completed questionnaires regarding symptoms related to motor and sensory PN. Overall, patients had a median serum 25D level of only 32 ng/ml; 42 % of patients were considered either 25D-deficient (<20.0 ng/mL; 16 % of patients) or 25D-insufficient (20.0-29.9 ng/mL; 26 %). Notably, we found that 25D-deficient MM patients were more likely to have severe PN (>grade 2) of both motor (p = 0.0415) and sensory (p = 0.0086) types although the overall incidence of PN was not higher in this patient population. CONCLUSION: These results show that the severity of peripheral neuropathy is associated with lower vitamin D levels and provides the rationale for monitoring vitamin D for myeloma patients especially those receiving drugs associated with the development of peripheral neuropathy.

Flow cytometry assessment of residual melanoma cells in tumor-infiltrating lymphocyte cultures.

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) is in development for the treatment of metastatic melanoma. In phase II clinical trials, patients with metastatic melanoma that received TIL after preconditioning had a 50-70% clinical response rate. The current approach to generate TIL is to culture melanoma enzyme digests in the presence of IL-2 for a 10- to 20-day period followed by 2 weeks of rapid expansion (REP). Prior to administration, cell therapies are characterized and tested for purity. TIL are characterized by CD3 surface marker expression, and purity is assessed by the amount of tumor remaining in culture. Evaluating TIL purity has traditionally been done by immunohistochemistry, which is often considered semiquantitative. To generate a quantitative assay, we used multiparameter flow cytometry to evaluate the presence of viable tumor cells by staining TIL populations with a viability dye and an antibody cocktail that detects intracellular tumor-antigens gp100, Mart-1, tyrosinase, S100, and surface tumor-antigen melanoma chondroitin sulfate proteoglycan (MCSP), and CD3 on T cells. Tumors were identified by gating on the viable CD3(-) population. Antigens in tumors were initially optimized with individual antibodies using both immunohistochemistry and flow cytometry. When eight different tumor cell lines were spiked into an activated T cell culture, flow cytometry was able to distinguish lymphocytes from tumors in all samples tested. Most importantly, the assay was able to detect melanoma cells in all enzyme digests (9/9) from patient samples. After IL-2-induced TIL expansion, there was a significant decrease in tumor cells; tumor cells were detected in only 2 of 12 samples. In eight IL-2-induced TIL samples that were further expanded in REP, no tumor cells were detected. We have demonstrated that flow cytometry is an alternative to immunohistochemistry for defining the purity of a TIL population.

Intravenous and topical intranasal bevacizumab (Avastin) in hereditary hemorrhagic telangiectasia.

Current treatment of severe epistaxis in patients with hereditary hemorrhagic telangiectasia is not durable in reducing the frequency and severity of bleeds. Recent reports have demonstrated marked improvement of epistaxis with administration of either intravenous or topical bevacizumab. We present the long-term outcome of a patient who received repeated treatments of intravenous bevacizumab followed by maintenance intranasal bevacizumab. We demonstrate durable control of epistaxis with intranasal bevacizumab. This allows delivery of bevacizumab effectively, reduces cost, and obviates the risk of systemic adverse effects related to bevacizumab.

gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma.

BACKGROUND: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).

Systemic therapy for cutaneous melanoma.

This article provides a review of the current medical management of patients with high-risk and metastatic cutaneous melanoma, including a review of the use of adjuvant interferon therapy and a discussion of adjuvant treatments under evaluation. The use of standard chemotherapeutic agents for metastatic disease is discussed, with an emphasis on developmental therapeutics using targeted agents. This discussion includes a review of the immune therapy for metastatic melanoma, including newer immunomodulatory agents and cellular therapeutics that are expected to significantly impact the care of these patients.

Lentivirus-mediated expression of mutant MGMTP140K protects human CD34+ cells against the combined toxicity of O6-benzylguanine and 1,3-bis(2-chloroethyl)-nitrosourea or temozolomide.

Lentiviral vectors are capable of efficiently transducing nondividing and slowly dividing cells, including hematopoietic stem cells, resulting in stable integration and sustained transgene expression. We constructed human immunodeficiency virus type 1-based self-inactivating lentiviral vectors to express either wild-type or an O6-benzylguanine (O6-beG)-resistant mutant form of the human O6-alkylguanine-DNA methyltransferase (MGMT; DNA-O6-methylguanine:[protein]-L-cysteine S-methyltransferase, EC 2.1.1.63) and transduced K562 and granulocyte colony-stimulating factor-mobilized human peripheral blood CD34+ cells. After transduction, K562 cells expressed high levels of MGMT as determined by Western blot, immunocytochemistry, and biochemical assay. A colony-forming survival assay showed significant protection against O6-beG plus 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) or temozolomide (TMZ) toxicity. Similarly, a single transduction of CD34+ cells resulted in a 13- to 14-fold increase in the level of MGMT expression. In comparison with non-transduced cells, mutant MGMTP140K-transduced CD34+ cells showed significant resistance against the combined toxicity of O6-beG with either TMZ or BCNU: there was an approximately 9-fold increase in the survival of colony-forming cells as indicated by the IC50 values after O6-beG plus TMZ treatment and an approximately 5-fold increase in the case of O6-beG plus BCNU treatment. These results show that lentivirus-mediated expression of MGMTP140K can efficiently protect the hematopoietic compartment against the combined toxicity of O6-beG plus TMZ or BCNU.

Immune Modulation in Cancer Patients After Adoptive Transfer of Anti-CD3/Anti-CD28-Costimulated T Cells-Phase I Clinical Trial.

Anti-CD3/anti-CD28 monoclonal antibody-coactivated T cells (COACTs) proliferate, secrete tumoricidal cytokines, and mediate non-major histocompatibility complex (MHC)-restricted cytotoxicity. This phase I study was done to determine the safety, maximum tolerated dose, technical limits of expansion, and modulation of immune functions in cancer patients given COACTs. Coactivated T cells were produced by stimulating peripheral blood mononuclear cells (PBMCs) with OKT3 anti-CD3 and 9.3 (anti-CD28)-coated beads in the presence of 100 IU interleukin (IL)-2 per milliliter for 14 days. The beads were removed after 4 days of culture. Ten courses of COACTs were given to eight patients with renal cell (1), ovarian (2), breast (1), and colorectal (4) carcinomas; two patients received two courses of COACTs. Patients were given up to 10 x 10 9 COACTs twice a week for 3 weeks without dose-limiting toxicities. Patients at the first and second dose levels received a mean total of 17.6 and 42.4 x 10 9 COACTs, respectively. After 14 days of culture, the COACTs contained a mean of 57.5% CD4 + cells and 42.5% CD8 + cells, exhibited non-MHC-restricted cytotoxicity, and produced significant amounts of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and granulocyte macrophage colony-stimulating factor (GM-CSF). Infusions were safe and induced measurable serum levels of IFNgamma, TNFalpha, and IL-4 in two patients. Peripheral blood mononuclear cells from patients who received COACTs secreted higher amounts of IFNgamma and GM-CSF on in vitro anti-CD3/anti-CD28 restimulation than PBMCs obtained before immunotherapy. The detection of cytokines in patient sera and enhanced in vitro production of cytokines by anti-CD3/anti-CD28-stimulated patient PBMCs after COACT infusions suggest that COACTs were modulating immune responses in cancer patients.