In-class transition from bortezomib-based therapy to IRd is an effective approach in newly diagnosed multiple myeloma.

Aim: To compare the effectiveness of in-class transition to all-oral ixazomib-lenalidomide-dexamethasone (IRd) following parenteral bortezomib (V)-based induction versus continued V-based therapy in US oncology clinics. Patients & methods: Non-transplant eligible patients with newly diagnosed multiple myeloma (MM) receiving in-class transition to IRd (N = 100; US MM-6), or V-based therapy (N = 111; INSIGHT MM). Results: Following inverse probability of treatment weighting, overall response rate was 73.2% with IRd versus 57.5% with V-based therapy (p < 0.0001). Median duration of treatment was 10.8 versus 5.3 months (p < 0.0001). Overall, 18/24% of patients discontinued IRd/V-based therapy due to adverse events. Conclusion: IRd after V-based induction was associated with significantly improved overall response rate and duration of treatment than continued V-based combination therapy. Clinical Trial Registration: US MM-6: NCT03173092; INSIGHT MM: NCT02761187 (ClinicalTrials.gov).

Phase 1 trial of CV301 in combination with anti-PD-1 therapy in nonsquamous non-small cell lung cancer.

CV301, a poxviral-based vaccine, has been evaluated in a phase 1 clinical trial (NCT02840994) and shown to be safe and immunologically active (phase 1a). Preclinical data support a combination of CV301 with programmed death-1 inhibitors, which has been evaluated in the phase 1b part of this trial and is reported here. Patients with advanced nonsquamous non-small cell lung cancer (NSCLC) without actionable genomic alterations received two priming doses of modified vaccinia Ankara-BN-CV301 (MVA) 4 weeks apart, followed by boosting doses of fowlpox-CV301 (FPV) at increasing time intervals for a maximum of 17 doses in combination with nivolumab for cohort 1 (C1) and 15 doses in combination with pembrolizumab for cohort 2 (C2). The primary objective was evaluation of safety and tolerability. Between October 2017 and September 14, 2018, patients were enrolled (C1: 4; median age: 64 years). Mean treatment duration was 332 days in C1 and 289 days in C2. CTCAE ≥grade 3 adverse events (AEs) were observed in four (100%) patients in C1 and three (37.5%) patients in C2. There was one death on trial. Immune-related AEs (irAEs) fulfilling criteria for a dose-limiting toxicity included 1 case of pneumonitis. Among 11 evaluable patients, 1 (9%) had a complete response, 1 (9%) had a partial response and 9 (82%) had stable disease. We conclude that CV301 administered with PD-1 inhibitors is safe and clinically active in patients with advanced NSCLC. The frequency or severity of AEs is not increased, including irAEs for each component of the combination.

Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination.

OBJECTIVE: To report a case of delayed methotrexate (MTX) elimination while receiving concomitant levetiracetam. CASE REPORT: A 46-year-old man with relapsed osteosarcoma of the base of the skull receiving high-dose MTX tolerated his first cycle of MTX with elimination to nontoxic MTX levels (≤0.1 µmol/L) within 90 hours. After hospital discharge, the patient experienced seizures secondary to brain metastasis and started on levetiracetam, which was continued as maintenance therapy. The patient experienced delayed MTX elimination during cycles 2, 3, and 4 while receiving levetiracetam. On average, elimination to nontoxic MTX levels took 130 hours (106-144 hours). Before the fifth cycle of MTX, lorazepam was substituted for the levetiracetam. MTX was eliminated to nontoxic levels within 95 hours. During all cycles, the patient received standard supportive care and serum creatinine remained stable. No other drugs known to interact with MTX were administered. DISCUSSION: This possible drug interaction has only been reported once in the pediatric population. With a score of 6 on the Drug Interaction Probability Scale for evaluating causation of drug interactions, it is probable that the delayed MTX elimination was caused by an interaction with levetiracetam. CONCLUSION: Coadministration of levetiracetam and MTX may result in delayed elimination of MTX, increasing the likelihood of toxicity. Consideration should be given to temporarily switching from levetiracetam to another antiepileptic (ie, lorazepam) to prevent this interaction. This is particularly important in those experiencing delayed elimination with prior cycles of concomitant MTX and levetiracetam or those at greater risk for MTX toxicity.

Sequencing of Anti-CD19 Therapies in the Management of Diffuse Large B-Cell Lymphoma.

Several second- and third-line immunotherapeutic options for patients with relapsed or refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplant are directed against the B-cell antigen cluster of differentiation 19 (CD19). The anti-CD19 monoclonal antibody tafasitamab, paired with the immunomodulator lenalidomide, mediates antibody-dependent cellular toxicity and phagocytosis; the antibody-drug conjugate loncastuximab tesirine delivers the DNA cross-linking agent tesirine via CD19 binding and internalization; and CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) products are engineered from autologous T cells. Although CD19 expression is assessed at diagnosis, clinically relevant thresholds of CD19 expression-which may not be detectable using current routine methodologies-have not been defined and may vary between CD19-directed treatment modalities. Determining optimal treatment sequencing strategies for CD19-directed therapy is hampered by the exclusion of patients who have received prior CD19-directed therapies from major clinical trials. Antigen escape, which is attributed to mechanisms including epitope loss and defective cell surface trafficking of CD19, is an important cause of CAR-T failure. Limited data suggest that CD19 expression may be maintained after non-CAR-T CD19-directed therapy, and retrospective analyses indicate that some patients with disease relapse after CAR-T may benefit from subsequent CD19-directed therapy. To date, clinical evidence on the effect of anti-CD19 therapy prior to CAR-T has been limited to small case series. Prospective studies and detailed analyses are needed to understand how pretreatment and posttreatment CD19 expression correlates with clinical responses to subsequent CD19-directed therapy to fully maximize treatment strategies.

Clinical research in the community.

Most patients with high-risk hematologic malignancies are treated in community oncology practices near their residence. This is partly due to patients' ardent desire to be closer to home and trust in local caregivers. Treatments are increasingly complex, even as initial therapy, and more so upon relapse. Improved outcomes in the past decade are largely available through clinical trials primarily offered through academic medical centers. Limited availability of clinical trials at community oncology practices is a major contributor to outcome disparities among minorities, rural, and elderly patients, all of whom are underrepresented in clinical trials. Between 2003 and 2023, the National Cancer Institute (NCI) established programs to address these challenges: the Community Clinical Oncology Program, Minority- Based Community Clinical Oncology Program, NCI Community Cancer Centers Program, and NCI Community Oncology Research Program. However, disparities have persisted, particularly for pharmaceutical-directed clinical research. Lack of representation in clinical research results in data absenteeism, data chauvinism and hallucination, and a delay in treatment availability for high-risk hematologic malignancies in community practice. To address this, the US Congress enacted the Food and Drug Administration Omnibus Act in 2022 to help establish diversity plans that would broaden clinical trial patient enrollment in the United States. We recommend using these initiatives in community oncology practices, including the adoption of the DRIVE strategy in collaboration with pharmaceutical companies, as well as using the NCI-established programs to promote clinical trial availability for patients with high-risk malignancies treated in community oncology practices.

In-class transition (iCT) of proteasome inhibitor-based therapy: a community approach to multiple myeloma management.

Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61-78). ORR increased from 62% at the end of induction to 80% following in-class transition (iCT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. iCT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL.

Feasibility of Long-term Proteasome Inhibition in Multiple Myeloma by in-class Transition From Bortezomib to Ixazomib.

BACKGROUND: The ongoing US MM-6 study is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral IRd (ixazomib-lenalidomide-dexamethasone) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence and duration while maintaining patients' health-related quality of life (HRQoL) and improving outcomes. PATIENTS AND METHODS: US community sites are enrolling non-transplant-eligible patients with newly diagnosed multiple myeloma (MM) with no evidence of progressive disease after 3 cycles of bortezomib-based therapy to receive IRd (up to 39 cycles or until progression or toxicity). The patients use mobile or wearable digital devices to collect actigraphy (activity and sleep) data and electronically complete HRQoL, treatment satisfaction and medication adherence questionnaires. The primary endpoint is progression-free survival. The key secondary endpoints include response rates and therapy duration. RESULTS: At the data cutoff, 84 patients had been treated (median age 73 years; 44% aged ≥ 75 years; 49% men; 15% Black or African American; and 10% Hispanic or Latino). Of the 84 patients, 62% were continuing therapy. The mean duration of total PI therapy was 10.1 months and for the IRd regimen was 7.3 months. With an 8-month median follow-up, the 12-month progression-free survival rate was 86% (95% confidence interval, 73%-93%) from both the start of bortezomib-based treatment and the start of IRd. The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after iCT. The IRd safety profile was consistent with previous clinical trial data, and HRQoL and treatment satisfaction were maintained. CONCLUSION: The patients included in the US MM-6 study are representative of the real-world US MM population. The use of iCT might permit prolonged PI-based therapy with promising efficacy, without impacting patients' HRQoL or treatment satisfaction.

Severe Hypoglycemia Caused by Lenalidomide.

Lenalidomide is commonly used for multiple myeloma as either induction or maintenance therapy. The agent is associated with a host of adverse effects, but hypoglycemia has only been reported in one phase I trial in patients with solid tumors. We describe a 74-year-old woman who experienced grade 3 hypoglycemia (blood glucose level 35 mg/dl) likely related to lenalidomide. Her medical history was significant for refractory myeloma and type 2 diabetes mellitus. Lenalidomide was started as maintenance therapy following autologous bone marrow transplantation. Approximately 3 years later, she developed refractory hypoglycemia necessitating hospital admission despite stopping antihyperglycemic agents 4 weeks prior to admission. Lenalidomide was withheld during her admission and restarted 2 days prior to discharge. Work-up for causes of persistent hypoglycemia was negative, and her glucose levels improved over her 26-day hospitalization. She was readmitted approximately one month later for hypoglycemia, and lenalidomide was permanently discontinued. Again, work-up for causes of hypoglycemia was negative, and her glucose levels stabilized over her hospitalization. After discontinuation of lenalidomide, hypoglycemia did not recur, and within 1 year the patient required reinitiation of antihyperglycemic medications to control her glucose levels. Given the resolution of hypoglycemia with lenalidomide discontinuation and return of hyperglycemia after restarting the agent, it is likely that lenalidomide was the cause of the patient's hypoglycemia. Use of the Naranjo adverse drug reaction probability scale indicated a definite relationship (score of 9) between the patient's development of grade 3 hypoglycemia and lenalidomide therapy. Although this adverse drug reaction had been previously reported with lenalidomide during phase I trials in patients with solid tumors, only grade 1 or 2 hypoglycemia was reported in three patients. To our knowledge, this is the first reported case of grade 3 hypoglycemia caused by lenalidomide.

Resection of a mature cystic teratoma of the liver harboring a carcinoid tumor.

Cystic teratomas are rare pluripotent embryonic tumors which most commonly originate in gonadal organs. Extra-gonadal cystic teratomas are exceedingly uncommon, accounting for only 1% of all cystic teratomas, and have been reported in unusual locations including the kidney, mediastinum and liver. These extra-ovarian cystic teratomas have also been known to harbor other neoplasms including carcinoid tumors. In this report, we describe a unique case of a hepatic cystic teratoma occurring as a combined tumor with a carcinoid in a young female. The patient underwent elective laparoscopic resection of her tumor after extensive radiographic and endoscopic work-up for chronic, non-localizable abdominal pain. We believe the carcinoid tumor arose de novofrom committed differentiation of a cell line within the teratoma, and not metastatic spread.

Denosumab Treatment for a Residual Giant Cell Tumor of the Clivus: A Case Report and Review of the Literature.

BACKGROUND: Giant cell tumors (GCTs) are a locally aggressive primary bone neoplasm of osteoclast-like cells. These lesions largely occur in the epiphyses of long bones, but there have been rare reports of occurrence in the pelvis, spine, or skull. Of those located in the skull, involvement of the clivus has been rarely reported. CASE DESCRIPTION: We present a case of an 18-year-old woman presenting with a third nerve palsy, found to have a lytic lesion of the upper clivus that was primarily treated with endoscopic endonasal resection. Her third nerve palsy resolved postoperatively, and subsequent histopathologic analysis revealed a GCT. Six-month postoperative magnetic resonance imaging (MRI) revealed progression of residual disease for which she was treated with adjuvant denosumab. This treatment resulted in a significant decrease in the tumor size. She subsequently underwent proton beam radiation. At 1-year postsurgery, the patient's MRI remained stable after completing denosumab and proton therapy. She was neurologically intact and had no issues from her treatment. CONCLUSIONS: Denosumab has demonstrated anti-GCT efficacy. In combination with proton therapy, it has the potential to spare a young, vulnerable population from adverse long-term effects of traditional adjuvant radiation therapy. To our knowledge, this is the first report of the use of denosumab in the treatment of GCT of the clivus in the United States.

I.V. ascorbic acid for treatment of apparent rasburicase-induced methemoglobinemia in a patient with acute kidney injury and assumed glucose-6-phosphate dehydrogenase deficiency.

PURPOSE: A case of apparent rasburicase-induced methemoglobinemia and acute kidney injury treated with i.v. ascorbic acid because of suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency is reported. SUMMARY: A 46-year-old African-American man with a recent diagnosis of multiple myeloma and renal insufficiency was admitted to the hospital with a cough, hemoptysis, and fatigue. His medical history included hypertrophic cardiomyopathy, ventricular tachycardia, attention deficit/hyperactivity disorder, and pleural effusion. No treatments for multiple myeloma were started before hospital admission. Levofloxacin 750 mg orally daily for possible pneumonia, lenalidomide 10 mg orally daily, and dexamethasone 20 mg orally weekly were administered. Plasmapheresis was also initiated. Laboratory test results revealed sustained hyperuricemia, which was believed to be due in part to tumor lysis, and a single dose of rasburicase 6 mg i.v. was administered. Subsequently, the patient experienced a decrease in oxygen saturation. Methemoglobinemia was suspected, and the patient's methemoglobin fraction was found to be 14.5%. The patient developed worsening shortness of breath and a drop in hemoglobin concentration, consistent with methemoglobinemia and hemolysis. Ascorbic acid 5 g i.v. every 6 hours was initiated for a total of six doses. Because the patient was assumed to have G6PD deficiency, which was later confirmed, methylene blue was avoided. Within 24 hours, the patient's oxygen saturation values and symptoms improved. CONCLUSION: A patient with apparent rasburicase-induced methemoglobinemia and acute kidney injury was treated with i.v. ascorbic acid (5 g every six hours for six doses) because of the possibility, later proved, that he had G6PD deficiency. The methemoglobinemia resolved without worsening of renal function.

Peripheral blood progenitor cell transplantation.

Peripheral blood progenitor cells (PBPCs) have become increasingly popular over the last 15 years as the source of hematopoietic stem cells for transplantation. In the early 1990s, PBPCs replaced bone marrow (BM) as the preferred source of autologous stem cells, and recently the same phenomenon is seen in the allogeneic setting. Under steady-state conditions, the concentration of PBPCs (as defined by CFU-GM and/or CD34+ cells) is very low, and techniques were developed to increase markedly this concentration. Such mobilization techniques include daily injections of filgrastim (G-CSF) or a combination of chemotherapy and growth factors. Leukapheresis procedures allow the collection of large numbers of circulating white blood cells (and PBPCs). One or two leukapheresis procedures are often sufficient to obtain the minimum number of CD34+ cells considered necessary for prompt and consistent engraftment (i.e., 2.5-5.0 x 10(6)/kg). As compared to BM, autologous transplants with PBPCs lead to faster hematologic recovery and have few, if any, disadvantages. In the allogeneic arena, PBPCs also result in faster engraftment, but at a somewhat higher cost of chronic graft-versus-host disease (GvHD). This may be a double-edged sword leading to both increased graft-versus-tumor effects and increased morbidity. The rapid advances in the study of hematopoietic, and even earlier, stem cells will continue to shape the future of PBPC transplantation.