Novel Pharmacological Treatment Options of Steroid-Refractory Graft-versus-Host Disease.

Background: Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplant. The mainstay of treatment is corticosteroids, which are ineffective in 30-50% of cases. Steroid-refractory GVHD (SR-GVHD) confers a poor prognosis, with high mortality rates despite appropriate therapy. While there is no reliable treatment for SR-GVHD, a variety of novel therapeutic options are slowly emerging and have yet to be examined simultaneously. Objectives: This review evaluates the potential of novel therapeutic options, as well as their efficacy and safety, for the treatment of SR-GVHD. Study Design. The literature search was conducted in PubMed, Cochrane, and Embase, employing MeSH terms and keywords. The studies had to be prospective phases 1, 2, or 3. We excluded retrospective and nonoriginal studies. Results: While the only approved drug for acute GVHD is ruxolitinib with an impressive overall response rate of 73.2% and a complete response of 56.3%, several monoclonal antibodies and other agents are currently under investigation, offering promising results. These include anti-CD2, anti-CD147, IL-2 antagonist, a mixture of anti-CD3 and anti-CD7 antibodies, anti-CD25, monoclonal antibody to a4b7 on T-cells, anti-CD26, pentostatin, sirolimus, denileukin diftitox, infliximab, itacitinib, and alpha-1 antitripsin. However, the toxicities associated with these novel drugs need further investigation. For chronic GVHD, approved options include ruxolitinib with an ORR of up to 62%, ibrutinib with an ORR of up to 77%, and belumosudil with an ORR of up to 77%. Meanwhile, emerging treatments include tyrosine kinase inhibitors such as nilotinib, rituximab, and low-dose IL-2, as well as axatilimab and pomalidomide. Conclusion: While their efficacy needs to be better evaluated through large-scale, multicenter, randomized clinical trials, these novel agents show potential and could provide a better alternative for SR-GVHD treatment in the future.

Isolated pulmonary metastases in pancreatic ductal adenocarcinoma: a review of current evidence.

Despite recent advances in cancer therapeutics, pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year overall survival of only 10%. Since either at or within a few months of diagnosis, most patients with PDAC will present with metastatic disease, a more individualized approach to select patients who may benefit from more aggressive therapy has been suggested. Although studies have reported improved survival in PDAC and isolated pulmonary metastasis (ISP) compared to extrapulmonary metastases, such findings remain controversial. Furthermore, the added benefit of pulmonary metastasectomy and other lung-directed therapies remains unclear. In this review, we discuss the metastatic pattern of PDAC, evaluate the available evidence in the literature for improved survival in PDAC and ISP, evaluate the evidence for the added benefit of pulmonary metastasectomy and other lung-directed therapies, identify prognostic factors for survival, discuss the biological basis for the reported improved survival and identify areas for further research.

Association of medical uninsurance with sociodemographic attributes in US cancer population: A cross-sectional study of NHANES data 2013 to 2018.

Medical uninsurance (MU) is associated with cancer disparities, particularly among underprivileged and minority sections of the United States. In this cross-sectional study of National Health and Nutritional Examination Survey (NHANES) data from 2013 to 2018, we evaluated sociodemographic attributes of MU disparity in the US cancer population. Those aged ≥20 years with a history of cancer and disclosed MU status were included. We calculated the descriptive statistics of the population stratified by insurance type and performed bivariate and multivariate logistic regression models to assess the association of sociodemographic attributes and MU and reported unadjusted (UOR) and adjusted odds ratios (AOR). Among the 1681 participants (US estimated, 25,982,352), 4.3% ± 0.62 were uninsured. Uninsured individuals were 13.5-year younger, largely female, less educated, and non-US born compared to insured individuals. Age (UOR: 0.94, 95% CI: 0.93-0.96), female sex (UOR: 3.53, 95% CI: 1.73-7.19), Hispanics (UOR: 4.30, 95% CI: 2.45-7.54),

The role of immunotherapy plus chemotherapy versus chemotherapy alone as first-line treatment for advanced non-small cell lung cancer: an updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Recently published randomized controlled trials (RCTs) showed improved overall survival (OS) and progression-free survival (PFS) with the combination of immunotherapy and chemotherapy as compared to chemotherapy alone in advanced non-small cell lung cancer (NSCLC). We aimed to provide a systematic review and meta-analysis of RCTs regarding the efficacy and safety of immunotherapy and chemotherapy combinations for advanced NSCLC. METHODS: On December 23rd, 2021, we searched databases for RCTs that reported PFS and OS as primary outcomes. RESULTS: We included 11 RCTs with 6,386 patients (3,850 in the combination therapy group and 2,536 in the chemotherapy group). Combination therapy was associated with an improvement in PFS (HR: 0.60; 95% CI: 0.54, 0.66; P < 0.00001) andOS (HR: 0.77; 95% CI: 0.68, 0.87; P ≤ 0.0001), compared to chemotherapy. There were no significant differences between both groups in terms of treatment-related adverse events (TRAEs) (RR: 1.07; 95% CI: 0.99, 1.16; P = 0.09). CONCLUSION: The combination of immunotherapy and chemotherapy as first-line treatment for advanced NSCLC significantly improved PFS and OS compared to chemotherapy alone without a significant increase in the overall TRAEs.

Incidence and comparative prognosis of cancers with metastasis to noncommon sites: A population-based study.

Primary tumors have common sites of metastasis such as lymph nodes, bones, liver, lungs, and brain; however, they can also metastasize to other uncommon sites such as adrenals, bone marrow, and skin among others. Our study aimed to investigate the relationship between uncommon sites of metastasis at the time of diagnosis and median survival in a number of primary tumors using the Surveillance, Epidemiology, and End Results (SEER) database. This retrospective cohort study conducted between September-October 2021 included patient-level SEER data for 2016-2018 using SEER Research Data, 9 Registries, Nov 2020 Sub (1975-2018). Descriptive analysis for complete cohort and median survival for each primary within the cohort was performed using R software. A total of 25,345 patients (females, 51.4%) were diagnosed with primary tumors with metastasis to uncommon sites at the time of diagnosis; the mean age at diagnosis was 68 years. Lung and bronchus primaries constituted the largest proportion of cohort (41.9%) that metastasized to uncommon sites, followed by nonHodgkin lymphoma-nodal (7.4%), pancreas (6.6%), stomach (3.7%), and ovarian (3.4%). The incidence of metastasis to uncommon sites was most common in respiratory cancers in ages 61-80 years (25%) and least in breast primaries in ages 18-40 years (0.1%), and was higher in Whites compared to other races. Regarding median survival, liver cancer with metastasis to uncommon sites had the worst prognosis (1 month), whereas small intestine tumors were associated with a better prognosis, median survival of 13 months. In this cohort study, the lung and bronchus cancers were the most common primaries metastasized to uncommon sites at diagnosis. The liver tumor had the worst survival compared to other tumors. These findings will help redirect the available screening tools to improve survival in patients with primary tumors with metastasis at diagnosis and may also play an essential role in future research and achieve a better prognosis for cancer patients.

Evidence-based recommendations for induction and maintenance treatment of newly diagnosed transplant-ineligible multiple myeloma patients.

There is increasing evidence regarding the role of various maintenance therapy (MT) strategies after initial induction to treat newly diagnosed transplant-ineligible patients with MM. We reviewed the literature on available regimens for patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM). Lenalidomide (R)-based regimens are still the front-line therapy, but there is an increasing use of bortezomib-based regimens. The MT regimen is mainly based on the initial induction regimen. MT has shown survival benefits compared with patients without maintenance therapy. The most common adverse effects of MT include anemia, neutropenia, thrombocytopenia, infections, and peripheral neuropathy. In conclusion, induction followed by maintenance based on lenalidomide, bortezomib, ixazomib, or daratumumab-based regimens has shown promising results. Therefore, it is essential to conduct more clinical trials to better understand the role of MT in the treatment of NDMM patients who are not candidates for autologous stem cell transplantation.

Emerging Role of Antibody-Drug Conjugates and Bispecific Antibodies for the Treatment of Multiple Myeloma.

Multiple myeloma (MM) is characterized by malignant proliferation of malignant plasma cells; it is the second most common hematological malignancy associated with significant morbidity. Genetic intricacy, instability, and diverse clinical presentations remain a barrier to cure. The treatment of MM is modernized with the introduction of newer therapeutics agents, i.e., target-specific monoclonal antibodies. The currently available literature lacks the benefits of newer targeted therapy being developed with an aim to reduce side effects and increase effectiveness, compared to conventional chemotherapy regimens. This article aims to review literature about the current available monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies for the treatment of MM.

Efficacy and safety of allogeneic hematopoietic stem cell transplant in adults with hemophagocytic lymphohistiocytosis: a systematic review of literature.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening disorder of the immune system. While familial HLH is usually seen in children, secondary HLH is more common in adults. Secondary HLH is associated with a wide variety of underlying conditions including infections, malignancy and autoimmune disorders. While HLH 94/04 protocol-based chemotherapy can be used for initial treatment, allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment modality for this disorder. In this systematic review, we analyzed available literature on the role of allo-HSCT in adolescent and adult patients using PubMed, Cochrane, Embase and ClinicalTrials.gov. A total of 11 retrospective studies evaluated the role of allo-HSCT for HLH. Allo-HSCT, when compared to non-HSCT approach, appears to be associated with reasonable efficacy and acceptable safety for adolescent and adult patients with HLH.

Efficacy and Safety of Daratumumab-based Regimens in Pretreated Light Chain (AL) Amyloidosis: A Systematic Review.

With recent advances in novel chemotherapeutic agents and increasing use of autologous hematopoietic stem cell transplant, there has been a significant improvement in outcomes for patients with AL Amyloidosis. Daratumumab, with its excellent safety and efficacy profile, appears to be an ideal treatment option for patients with newly diagnosed as well as relapsed refractory AL amyloidosis. In this systematic review, we analyzed the published literature on the role of Daratumumab in pretreated relapsed and refractory AL-amyloidosis patients using PubMed, Embase, Cochrane, and clinicaltrials.gov databases. A total of 16 studies evaluated the role of Daratumumab as monotherapy (DMT) or in combination with other chemotherapeutic agents (DCT). DMT and DCT were associated with promising efficacy with hematologic and organ responses (cardiac/renal) seen in 50%-90% and 50%-80% of the patients, respectively. Daratumumab appeared to be well tolerated with no significant treatment-related adverse events as DMT or DCT.

Secondary hemophagocytic lymphohistiocytosis due to nivolumab/ipilimumab in a renal cell cancer patient-A case report.

Secondary immune-related hemophagocytic lymphohistiocytosis is a rare but life-threatening complication of immune checkpoint inhibitors. HLH-2004 and HLH-1994 guidelines originally developed for primary HLH are the only available guidelines. It has proven to have a good prognosis if diagnosed promptly with discontinuation of immunotherapy and treated with corticosteroid monotherapy.

Efficacy and Toxicity Profile of Carfilzomib-Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review.

Carfilzomib (CFZ) is a proteasome inhibitor currently approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Multiple trials are ongoing to evaluate its efficacy and safety in newly diagnosed multiple myeloma (NDMM). The use of CFZ-based two- or three-drug combination regimens as induction for the management of NDMM is an emerging approach. CFZ-based regimens include combinations of immunomodulators, alkylating agents, and monoclonal antibodies along with dexamethasone. In this review, we assess the efficacy and toxicity of CFZ-based regimens in NDMM. We reviewed a total of 27 studies (n=4538 patients) with overall response rates (ORR) ranging between 80% and 100%. Studies evaluating the combination of CFZ with daratumumab reported an ORR of approximately 100%. Achievement of minimal residual disease (MRD) negativity, measured by multi-parameter flow cytometry (MPFC), ranged between 60% and 95% in 4 (n=251) out of 6 studies that measured MRD-negativity. The interim results of the ENDURANCE trial failed to show superior efficacy and progression-free survival (PFS) of carfilzomib-lenalidomide when compared to bortezomib-lenalidomide combination, albeit with a lower incidence of neuropathy. Hematological toxicity was the most common adverse event observed with these regimens, and the most common non-hematological adverse events were related to cardiovascular and electrolyte disturbances. We need to further evaluate the role of CFZ in NDMM by conducting more Phase III trials with different combinations.

Role of Venetoclax in the Treatment of Relapsed and Refractory Multiple Myeloma.

Biomarker-driven targeted therapies have been an area of exploration for innovative therapeutic options in oncology. B-cell lymphoma-2 (BCL-2) protein is an anti-apoptotic protein expressed on the clonal plasma cells in patients with multiple myeloma (MM). MM subsets with t (11;14) have overexpression of BCL-2 and can benefit from venetoclax (VEN) when used either alone or in combination with other chemotherapeutic agents with an overall response rate (ORR) ranging from 40% to 100%. The most commonly reported grade ≥ 3 adverse effects include cytopenias and gastrointestinal side effects. This review highlights the meaningful efficacy and tolerable safety of VEN monotherapy and its combination regimens in the treatment of relapsed refractory MM.

Profile and Management of Toxicity of Selinexor and Belantamab Mafodotin for the Treatment of Triple Class Refractory Multiple Myeloma.

Treatment options are limited for multiple myeloma patients who have developed four/five drug-refractory disease. Selinexor (Sel) and belantamab mafodotin (belamaf) were recently approved by the US FDA for treatment of RRMM. The toxicity profile of these drugs is a concern since these agents are used in patients who have already undergone multiple lines of treatment. In this review, we discuss the toxicity profile and strategies for the management of toxicities of Sel and belamaf for the treatment of RRMM. We conducted a comprehensive literature search on PubMed, Embase, Cochrane, and Clinicaltrials.gov using the terms "selinexor", "belantamab", "belamaf", and "multiple myeloma" without applying any limitations based on the date of the study, language, or country of origin. The most common hematological toxicity associated with these two drugs is thrombocytopenia. Cytopenias, constitutional symptoms, gastrointestinal effects, and hyponatremia are the major toxicities of Sel. Keratopathy and anemia are the major toxicities of belamaf. Treatment modifications and dose interruption are usually needed when side effects are more than grade II. As these are newer drugs with limited data, continuous surveillance and monitoring are warranted during the treatment course with early mitigation strategies.

Lurbinectedin-Induced Tumor Lysis Syndrome in Small Cell Neuroendocrine Cancer of the Cecum: A First-Ever Case Report.

BACKGROUND Lurbinectedin (Lurbi) was first approved in June 2020 for metastatic small cell lung cancer (SCLC) patients with progression following platinum-based chemotherapy. Extrapulmonary small cell neuroendocrine cancers (SCNECs) are treated with regimens used for SCLCs. Tumor lysis syndrome (TLS) in solid SCLCs and SCNECs following Lurbi use has not been reported in the literature so far. CASE REPORT We report a case of Lurbi-induced TLS in a patient with metastatic SCNEC of the cecum following a single intravenous dose of Lurbi 3.2 mg/m2. She presented to the hospital with abdominal pain, anuria, and grade 4 TLS. She required emergent hemodialysis due to acute renal failure. Our patient had a high Ki-67 proliferation index (95%), harbored a huge disease burden, and had bilateral renal metastasis, thus making her more susceptible to develop TLS. CONCLUSIONS Although data regarding the occurrence of TLS due to Lurbi in solid tumors are scarce, it remains a potential complication of Lurbi in neuroendocrine tumors with high proliferation index and large tumor burden.

Ocular Toxicity of Belantamab Mafodotin, an Oncological Perspective of Management in Relapsed and Refractory Multiple Myeloma.

Belantamab mafodotin (belamaf), an antibody-drug conjugate approved for the treatment of relapsed and refractory multiple myeloma (RRMM), is an anti B-cell maturation antigen (BCMA) agent. DREAMM-1, a first in-human trial of belamaf, reported several ocular toxicities requiring dose adjustments, dose delays and treatment discontinuations. In DREAMM-1, 53% of patients in part-1 and 63% of patients in part-2 had ocular toxicity. Similarly, 73% of patients in DREAMM-2 had keratopathy (71% in 2.5 mg/kg versus 75% in 3.4 mg/kg) with the most common symptoms being blurred vision and dry eyes. Ocular toxicity of belamaf is attributed to microtubule-disrupting monomethylauristatin-F (MMAF), a cytotoxic payload of the drug that causes an off-target damage to the corneal epithelial cells. Ocular adverse events (AEs) of belamaf are more frequent at higher doses compared with lower doses. Higher belamaf dose, history of dry eyes and soluble BCMA are associated with increased risk of corneal toxicity. Absence of ocular symptoms does not exclude the possibility of belamaf-induced ocular toxicity, so patients need slit lamp and Snellen visual acuity testing to detect microcytic-like epithelial changes and visual decline. Corticosteroid eyes drops for 4-7 days prior to belamaf dose do not prevent ocular AEs and may cause steroid-related AEs instead. Keratopathy and Visual Acuity scale (KVA) is recommended to document the severity of belamaf-induced ocular toxicity and make treatment adjustments. Management of toxicity includes dosage modifications, treatment interruption or discontinuations and preservative-free artificial tears along with close ophthalmology and hematology-oncology follow-ups.

Relapsed breast cancer complicated by isolated brain metastasis.

The most common etiology of malignant brain tumors is metastatic lesions. They usually present as multiple lesions at the gray-white matter junction. However, they can unconventionally present as a single space-occupying lesion mimicking meningioma.

Endoscopic retrograde cholangiopancreatography guided interventions in the management of pancreatic cancer.

Pancreatic cancer is the leading cause of cancer-related morbidity and mortality with an overall five-year survival of less than 9% in the United States. At presentation, the majority of patients have painless jaundice, pruritis, and malaise, a triad that develops secondary to obstruction, which often occurs late in the course of the disease process. The technical advancements in radiological imaging and endoscopic interventions have played a crucial role in the diagnosis, staging, and management of patients with pancreatic cancer. Endoscopic retrograde cholangiopancreatography (ERCP)-guided diagnosis (with brush cytology, serial pancreatic juice aspiration cytologic examination technique, or biliary biopsy) and therapeutic interventions such as pancreatobiliary decompression, intraductal and relief of gastric outlet obstruction play a pivotal role in the management of advanced pancreatic cancer and are increasingly used due to improved morbidity and complication rates compared to surgical management. In this review, we highlight various ERCP-guided diagnostic and therapeutic interventions for the management of pancreatic cancer.

Paclitaxel-Induced Palmar-Plantar Erythrodysesthesia.

Palmar-plantar erythrodysesthesia (PPE) is an uncommon adverse event with paclitaxel. We report a case of PPE due to paclitaxel to create awareness and review management strategies. A 61-year-old female with locally advanced lobular breast cancer was started on neoadjuvant chemotherapy with four cycles of dose-dense doxorubicin and cyclophosphamide. She completed these chemotherapy cycles uneventfully and was started on weekly paclitaxel (80mg/m2) with a gap of two weeks. After receiving the sixth dose of paclitaxel, the patient presented with erythema, swelling, and discomfort of her hands and feet, interfering with her quality of life due to difficulty in carrying out daily routine activities. The changes were acute, occurred within a few days after the sixth dose of paclitaxel, and were consistent with PPE grade 2. Paclitaxel was discontinued, and the patient was switched to docetaxel every three weeks for two cycles. She used emollients and moisturizing creams for her local symptoms, after stopping paclitaxel, erythema, swelling, and discomfort of her hands and feet resolved within two weeks. She did not have a recurrence of these symptoms with docetaxel. Paclitaxel can cause PPE. Its incidence in the literature might be underreported. Discontinuation of paclitaxel can reverse skin toxicity and improve patient's quality of life.

Advances in maintenance strategy in newly diagnosed multiple myeloma patients eligible for autologous transplantation.

INTRODUCTION: Multiple myeloma (MM) lacks curative therapy. Therefore, researchers continue to conduct studies in an effort to improve progression-free survival (PFS) and overall survival (OS). Maintenance therapy (MT) after autologous stem cell transplant (ASCT) was extensively studied in the last decade and now considered a standard approach. AREAS COVERED: This review evaluated the evidence and updates on various maintenance agents in newly diagnosed multiple myeloma (NDMM) after ASCT. Articles were searched on PubMed and Embase that were published in last 10 years. Both clinical trials and observational studies were evaluated. EXPERT OPINION: Maintenance strategy after ASCT has consistent PFS benefit but lacks conclusive OS improvement. Lenalidomide is superior to thalidomide given reduced neurotoxicity. OS advantage is controversial for both due to inconsistent evidence. Lenalidomide may confer a PFS advantage even at lower doses due to toxicity with higher doses. Bortezomib-based maintenance has some evidence for OS benefit in high-risk MM (HRMM) and renal dysfunction. Ixazomib has preliminary promising results. Two or three drug combinations for MT are potentially safe and more effective, particularly in HRMM although data on this subject is still evolving. Efficacy of various MT regimens in terms of minimal residual disease status needs to be further investigated.

Single-Agent Cyclosporine for Graft-versus-Host Disease Prophylaxis in Patients with Acquired Aplastic Anemia Receiving Fludarabine-Based Conditioning.

Cyclosporine (CsA) combined with short-course methotrexate is considered standard-of-care graft-versus-host disease (GVHD) prophylaxis for patients with severe aplastic anemia (AA) who undergo transplantation using cyclophosphamide (Cy) plus anti-thymocyte globulin (ATG) conditioning. However, there is no consensus on optimal post-transplant GVHD prophylaxis for patients undergoing matched related donor (MRD) transplantation using fludarabine (Flu)-based conditioning. We conducted a single-center retrospective analysis of patients with acquired AA (n = 106) undergoing MRD transplantation from July 2007 through January 2019. All patients received Flu-Cy-ATG conditioning and single-agent CsA as GVHD prophylaxis. Median age of the study cohort was 20 years (range, 3 to 52) and male to female ratio was 3.8:1. Median time from diagnosis to transplant was 11.5 months (range, 2.8 to 62). Graft source was bone marrow harvest in 71 (68%), combined bone marrow and peripheral blood stem cells in 34 (31%), and peripheral blood alone in 1 (1%) patient. Cumulative incidence of neutrophil engraftment at day 28 was 93.4% (95% confidence interval [CI], 87.3% to 97.1%) while that of platelet engraftment at day 100 was 90.5% (95% CI, 84% to 96%). Cumulative incidence of primary graft failure at day 28 was 6.6% (95% CI, 4% to 8%) while secondary graft failure occurred at a median of 190 days (range, 90 to 415) at a cumulative incidence of 3.7% (95% CI, 2% to 5%). Cumulative incidence of grade II to IV acute GVHD at day 100 was 3.8% (95% CI, 1.4% to 9.9%), while a 1-year probability of chronic GVHD was calculated as 7.5% (95% CI, 2.6% to 15%). Median follow-up post-transplant was 61 months (range, 6 to 144). Overall survival was 84.9%, disease-free survival was 80.2%, and GVHD-free relapse-free survival was 76.3%. This study indicates that single-agent cyclosporine is a feasible option for GVHD prophylaxis in MRD hematopoietic stem cell transplantation using Flu-Cy-ATG conditioning and is associated with very low rates of acute and chronic GVHD.