Chemotherapy-free treatment targeting fusions and driver mutations in KRAS wild-type pancreatic ductal adenocarcinoma, a case series.

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established. Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS-WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients. Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease (n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315-648 genes for tissue) between years 2015 and 2021. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one with a druggable EGFR (EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively. Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

Comprehensive genomic profiling: Does timing matter?

Purpose: There is variability in utilization of Comprehensive Genomic Profiling (CGP) in most of the metastatic solid tumors (MST). We evaluated the CGP utilization patterns and its impact on outcomes at an academic tertiary center. Patients and Methods: Institutional database was reviewed for CGP data in adult patients with MST between 01/2012 - 04/2020. Patients were categorized based on interval between CGP and metastatic diagnosis; 3 tertiles of distribution (T1-earliest to the diagnosis, T3-furthest), and pre-mets (CGP performed prior to diagnosis of metastasis). Overall survival (OS) was estimated from the time of metastatic diagnosis with left truncation at the time of CGP. Cox regression model was used to estimate the impact of timing of CGP on survival. Results: Among 1,358 patients, 710 were female, 1,109 Caucasian, 186 Afro-Americans, and 36 Hispanic. The common histologies were lung cancer (254; 19%), colorectal cancer (203; 15%), gynecologic cancers (121; 8.9%), and pancreatic cancer (106; 7.8%). Time interval between diagnosis of metastatic disease and CGP was not statistically significantly different based on sex, race and ethnicity after adjusting for histologic diagnoses with 2 exceptions - Hispanics with lung cancer had delayed CGP compared to non-Hispanics (p =0.019) and females with pancreas cancer had delayed CGP compared to males (p =0.025). Lung cancer, gastro-esophageal cancer and gynecologic malignancies had better survival if they had CGP performed during the first tertile after metastatic diagnosis. Conclusion: CGP utilization across cancer types was equitable irrespective of sex, race and ethnicity. Early CGP after metastatic diagnosis might have effect on treatment delivery and clinical outcomes in cancer type with more actionable targets.

Interim Positron Emission Tomography During Frontline Chemoimmunotherapy for Follicular Lymphoma.

While most patients with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of patients will experience early progression, which is associated with poor subsequent outcomes. Novel biomarkers are needed to identify high-risk patients earlier. We hypothesized that interim positron emission tomography (PET) would predict progression-free survival (PFS) in this population. We retrospectively identified 128 patients with grade 1-3A FL who had an interim PET after 2-4 cycles of frontline CIT at 2 academic centers. PET scans were analyzed using Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Interim PET DS was a significant predictor of PFS (P < 0.003). Patients with a DS of 3 had outcomes similar to those of patients with a DS of 4, so were categorized as PET-positive for additional analyses. Interim PET remained a strong predictor of PFS (DS 3-5, hazard ratio [HR] 2.4, P = 0.006) in a multivariable analysis and was also an early predictor of both a positive end-of-treatment PET (P < 0.001) and progression of disease within 24 months (POD24) (P = 0.006). An optimal ΔSUVmax cutoff of 75% was selected using the bootstrap method. ΔSUVmax <75% was also a significant predictor of PFS on univariable and multivariable analyses (HR 2.8, P < 0.003). In a separate cohort of 50 patients with high-grade FL, interim PET interpreted using either DS (P < 0.001) or ΔSUVmax75% (P = 0.034) was also a significant predictor of inferior PFS. In conclusion, interim PET is an independent predictor of PFS and may be useful as a tool for response-adapted treatment strategies in FL.

Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation.

Improved biomarkers are required to guide the optimal use of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples, post-ASCT peripheral blood mononuclear cell (PBMC), and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in of 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, P < .001) and inferior overall survival (52% vs 68%, P = .05). The sensitivity and specificity of ASC MRD positivity for progression and death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in multivariable analysis (hazard ratio [HR], 3.7; P < .001). Post-ASCT surveillance MRD testing of plasma, but not PBMC samples, reliably identified patients with an impending relapse. A positive plasma MRD result was associated with inferior PFS (HR, 3.0; P = .016) in a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range, 0-518 days). In conclusion, the detection of MRD in ASC samples is associated with a very high risk of relapse, justifying alternative treatment strategies or trials of novel consolidation options in these patients. Furthermore, post-ASCT MRD monitoring may facilitate the evaluation of the early initiation of treatment at molecular relapse. This trial has been registered at www.clinicaltrials.gov as #NCT02362997.

Impact of Chronic Kidney Disease and Acute Kidney Injury on Safety and Outcomes of CAR T-Cell Therapy in Lymphoma Patients.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapy is standard-of-care in relapse/refractory aggressive B-cell non-Hodgkin lymphoma. There are limited data regarding the impact of pre-existing chronic kidney disease (CKD) and acute kidney injury (AKI) post CAR-T and we sought to evaluate these in our patients. METHOD: In this single center retrospective analysis CKD cohort was defined KDIGO staging with eGFR of <60 mL/min/1.73 m2 (Stage ...3) at the time of pre-CAR-T assessment. Remaining patients constituted the no CKD group. AKI was defined by CTCAEv.4 and data were abstracted through Day 100 post-CAR-T therapy. The primary outcome was impact of pre-existing CKD on progression-free survival (PFS), overall survival (OS) and adverse events. Additionally, we also analyzed the impact of AKI on PFS and OS. RESULTS: Thirty-two patients were identified with 7 having pre-existing CKD. Among the patients with or without CKD, the median PFS was 8.8 and 2.9 months respectively (pvalue 0.78). The median OS was 10 and 7 months respectively (p-value 0.64). AKI developed in a total of 9 patients (29%) post CAR-T, including 7 patients without CKD at baseline. The median PFS was 3.6 and 2.8 months for patients not developing AKI and developing AKI (p-value 0.84). Median OS in similar order was 10 and 3.9 months respectively (p-value 0.2). On univariate analysis, creatinine at baseline (p-value 0.018) and ICANS grade 2+ (p-value 0.016) were associated with an increased risk of developing AKI. CONCLUSIONS: CKD or AKI after CAR-T showed no impact on post procedure OS and PFS.

CAR T-cell therapy for secondary CNS DLBCL.

Management of secondary central nervous system (SCNS) involvement in relapsed or refractory aggressive B-cell lymphomas remains an area of unmet medical need. We report a single-center retrospective analysis of 7 adult patients with SCNS lymphoma (SCNSL) who underwent chimeric antigen receptor (CAR) T-cell therapy for their refractory disease, and we describe the safety of whole brain radiation therapy (WBRT) as a bridging therapy. Six patients (85.7%) achieved a complete response at day 28, and 1 patient had progressive disease. The median progression-free survival was 83 days (range, 28-219 days), and median overall survival was 129 days (range, 32-219 days). Three patients died as a result of disease progression. Of the 5 patients who received WBRT as bridging therapy, 3 had no immune effector cell-associated neurotoxicity syndrome (ICANS), but 2 patients had grade 1 or grade 3 ICANS. No grade 4 ICANS was reported in this subset of patients. We conclude that SCNSL should not preclude patients from receiving CAR T-cell therapy as a treatment option because of concerns regarding ICANS, and bridging with WBRT is not associated with increased ICANS.

Pulmonary Lymphangitic Spread of Multiple Myeloma as Early Relapse after Autologous Stem Cell Transplantation.

Clinical relapses early after autologous stem cell transplantation portrays an inferior clinical outcome. Early relapse in this setting with extramedullary disease (EMD) of lung involvement in multiple myeloma is rare. To our knowledge, this is the first reported case of lymphangitic spread of myeloma with pulmonary parenchymal and pleural involvement occurring at first relapse.

Extracorporeal Membrane Oxygenation with Right Ventricular Assist Device for COVID-19 ARDS.

BACKGROUND: Right ventricular failure is an underrecognized consequence of COVID-19 pneumonia. Those with severe disease are treated with extracorporeal membrane oxygenation (ECMO) but with poor outcomes. Concomitant right ventricular assist device (RVAD) may be beneficial. METHODS: A retrospective analysis of intensive care unit patients admitted with COVID-19 ARDS (Acute Respiratory Distress Syndrome) was performed. Nonintubated patients, those with acute kidney injury, and age > 75 were excluded. Patients who underwent RVAD/ECMO support were compared with those managed via invasive mechanical ventilation (IMV) alone. The primary outcome was in-hospital mortality. Secondary outcomes included 30-d mortality, acute kidney injury, length of ICU stay, and duration of mechanical ventilation. RESULTS: A total of 145 patients were admitted to the ICU with COVID-19. Thirty-nine patients met inclusion criteria. Of these, 21 received IMV, and 18 received RVAD/ECMO. In-hospital (52.4 versus 11.1%, P = 0.008) and 30-d mortality (42.9 versus 5.6%, P= 0.011) were significantly lower in patients treated with RVAD/ECMO. Acute kidney injury occurred in 15 (71.4%) patients in the IMV group and zero RVAD/ECMO patients (P< 0.001). ICU (11.5 versus 21 d, P= 0.067) and hospital (14 versus 25.5 d, P = 0.054) length of stay were not significantly different. There were no RVAD/ECMO device complications. The duration of mechanical ventilation was not significantly different (10 versus 5 d, P = 0.44). CONCLUSIONS: RVAD support at the time of ECMO initiation resulted in the no secondary end-organ damage and higher in-hospital and 30-d survival versus IMV in specially selected patients with severe COVID-19 ARDS. Management of severe COVID-19 ARDS should prioritize right ventricular support.

Pandemic Perspective: Commonalities Between COVID-19 and Cardio-Oncology.

Overlapping commonalities between coronavirus disease of 2019 (COVID-19) and cardio-oncology regarding cardiovascular toxicities (CVT), pathophysiology, and pharmacology are special topics emerging during the pandemic. In this perspective, we consider an array of CVT common to both COVID-19 and cardio-oncology, including cardiomyopathy, ischemia, conduction abnormalities, myopericarditis, and right ventricular (RV) failure. We also emphasize the higher risk of severe COVID-19 illness in patients with cardiovascular disease (CVD) or its risk factors or cancer. We explore commonalities in the underlying pathophysiology observed in COVID-19 and cardio-oncology, including inflammation, cytokine release, the renin-angiotensin-aldosterone-system, coagulopathy, microthrombosis, and endothelial dysfunction. In addition, we examine common pharmacologic management strategies that have been elucidated for CVT from COVID-19 and various cancer therapies. The use of corticosteroids, as well as antibodies and inhibitors of various molecules mediating inflammation and cytokine release syndrome, are discussed. The impact of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is also addressed, since these drugs are used in cardio-oncology and have received considerable attention during the COVID-19 pandemic, since the culprit virus enters human cells via the angiotensin converting enzyme 2 (ACE2) receptor. There are therefore several areas of overlap, similarity, and interaction in the toxicity, pathophysiology, and pharmacology profiles in COVID-19 and cardio-oncology syndromes. Learning more about either will likely provide some level of insight into both. We discuss each of these topics in this viewpoint, as well as what we foresee as evolving future directions to consider in cardio-oncology during the pandemic and beyond. Finally, we highlight commonalities in health disparities in COVID-19 and cardio-oncology and encourage continued development and implementation of innovative solutions to improve equity in health and healing.

First Case of Topical 5-FU Therapy for Cutaneous Metastasis in a Patient with Colon Cancer.

Cutaneous metastasis from colon cancer is rare, occurs in less than 6% of patients and its associated with poor prognosis. Most often it presents in the abdomen, inguinal or perineal regions, supraclavicular area, and less commonly on the face, neck, scalp, and prior surgical sites. We present a case of a 41-year-old female with colon cancer who developed cutaneous metastases to the scalp, and was treated with topical 5-FU and radiation therapy. Treatment options for cutaneous metastases usually include systemic therapy, topical chemotherapy, surgical excision, or radiation. Our case is probably the first report who was treated with topical 5-FU in addition to radiation therapy. This treatment modality is easy to use and we would recommend clinical trials to be conducted to further study the use of topical 5-FU.

Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report.

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Validation of the Khorana Score to Assess Venous Thromboembolism and Its Association with Mortality in Cancer Patients: A Retrospective Community-based Observational Experience.

INTRODUCTION: Khorana score (KS) stratifies patients into low, intermediate, and high risk groups for venous thromboembolism (VTE). We examined the generalizability of the KS to risk of VTE and association with mortality. METHODS: A retrospective cohort study was conducted at Mount Auburn Hospital, Cambridge, Massachusetts. Patients aged 18 years or older undergoing chemotherapy were included. All patients were evaluated for a six-month period. Primary study endpoints were VTE or mortality. RESULTS: Some 277 participants were included with a mean age of 63.95 (standard deviation, SD ± 12.47). The incidence proportion was 6.13% and a total of 17 VTE events were reported over a 2.5-year period. Compared to those with a low KS (0), those with a high KS (3 or above) had 6.4 times (p=0.032) while with an intermediate KS (1-2) had 2.6 times the odds of having a VTE event (p=0.22). Those who had a VTE had 4.03 times the odds of death compared to those who did not have a VTE (p=0.006). Compared to those with a low KS, those with a high KS had 5.7 times (p=0.02) the odds of six-month mortality and 5.04 odds (p=0.001) of mortality at any time. CONCLUSION: High KS was associated with increased odds of VTE and mortality in our study.

Outcomes and Toxicities of Programmed Death-1 (PD-1) Inhibitors in Hodgkin Lymphoma Patients in the United States: A Real-World, Multicenter Retrospective Analysis.

BACKGROUND: Although classical Hodgkin lymphoma (cHL) is highly curable, 20%-30% of patients will not be cured with conventional treatments. The programmed death-1 (PD-1) inhibitors (PD-1i) nivolumab and pembrolizumab have been Food and Drug Administration-approved for relapsed/refractory (R/R) cHL. There is limited data on the real-world experience with PD-1i in cHL and it is unknown whether fewer selected patients treated with PD-1i derive benefits similar to those observed in published trials. MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of R/R cHL patients treated with PD-1i in the nontrial setting. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) in this population. Secondary objectives were to characterize response rates, toxicities, discontinuation patterns, and post-PD-1i therapies. RESULTS: The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses. CONCLUSION: To our knowledge, this analysis is the first describing real-world experience with PD-1i in cHL patients in the U.S. Here, we demonstrate similar response rates compared to prior studies. The toxicity profile of PD-1i was similar to that seen in previous studies; we further describe toxicity patterns in those with prior autoimmune disease or allogeneic transplant. Post-PD-1i systemic therapies appear active. These results support the effectiveness and tolerability of PD-1i therapy in R/R cHL in a real-world setting. IMPLICATIONS FOR PRACTICE: Two PD-1 inhibitors have recently been approved for patients with relapsed/refractory classical Hodgkin lymphoma based on results from nonrandomized clinical trials. However, to date, there have been no studies evaluating the effectiveness and toxicity profile of these drugs in the real-world setting in the U.S. The present study demonstrates that patients treated in a real-world context experience similar rates of overall effectiveness compared with published clinical trials. Patients who discontinue PD-1 inhibitors may experience clinical responses to subsequent treatment with systemic chemotherapy or targeted therapy. This study provides clinicians with further insight into the effectiveness and tolerability of PD-1 inhibitors and suggests that when patients progress while on these drugs, conventional systemic chemotherapy may be an effective treatment option.

Continuing Medical Education: A Cross Sectional Study on a Developing Country's Perspective.

To determine the attitude of general practitioners towards continuing medical education (CME) and reasons motivating or hindering them from attending CME procedures, we conducted a cross-sectional survey from November 2013 to April 2014 in Karachi. Three hundred general practitioners who possessed a medical license for practice in Pakistan filled a pre-designed questionnaire consisting of questions pertaining to attitudes towards CME. Data was entered and analyzed using SPSS v16.0. 70.3% (n = 211) of the participants were males. Mean age was 47.75 ± 9.47 years. Only 67.33% knew about CME and only 52% had attended a CME session. Reasons for attending CME procedures reported were: need for updating knowledge, skills and competencies (67.30%), opportunity to meet colleagues (18.58%) and presenting scientific papers (8.97%). Mean Likert score was 1.67 (±0.667) for those who thought CME is worthwhile and 1.44 (±0.686) for those who consider their clinical duties as the major hurdle in attending CME procedures. Most common cause for not attending CME was lack of knowledge (32.66%) followed by time constraint (24%). Most physicians were not sufficiently informed about the potential benefits of CME and had never attended a CME session. Most common reason for attending CME procedures reported was need for updating knowledge, skills and competencies while reasons hindering physicians from attending CME were lack of knowledge and time constraint.

Pulmonary Tuberculosis Versus Recurrent Chemotherapy-Induced Pneumonitis: A Clinical Dilemma.

Chemotherapy-induced lung toxicity can affect pulmonary parenchyma, pleura, airways, pulmonary vascular system, mediastinum or the neuromuscular system that is responsible for respiration. Chemotherapy-induced pulmonary toxicity is a diagnosis of exclusion. When the patients with malignancies develop pulmonary toxicity such as pneumonitis and distinguishing it from alternative diseases such as infectious, thrombotic, cardiac, malignant or exacerbation of chronic lung conditions can be difficult. Moreover, such patients are often immunosuppressed, physically stressed from the underlying disease and the cancer treatment and hence, more susceptible to usual and unusual or opportunistic infections. We describe a patient with pancreatic cancer who was assumed to develop recurrent chemotherapy-induced pneumonitis to various agents, including irinotecan and docetaxel, but subsequently proved to have reactivation of tuberculosis (TB). With tuberculosis not being uncommon in cancer patients, we now believe that his symptoms could all have been because of an active tuberculosis infection, especially with his latent TB history and pulmonary symptoms. Information about the link between the treatment of solid-organ cancers and TB is very limited. Our case underlines the recognition about this link of chemotherapy and TB as well as remind us of the lack of widely accepted and established standards for both screenings for latent TB and for the treatment of active TB in the patients undergoing systemic treatment. A simple test such as a tuberculin skin test or QuantiFERON-TB Gold test can be used to rule out latent TB before beginning radiotherapy or chemotherapy in these patients. Clinicians must be cognizant of this condition to prevent further morbidity and mortality in these cancer patients and include activated TB in the differential diagnosis of pulmonary toxicity suspected in a patient undergoing chemotherapy with unexplained pulmonary findings.