Clonality Determination by Detecting Unmodified Monoclonal Serum Free Light Chains Using On-Probe Extraction Coupled with Liquid Chromatography-High-Resolution Mass Spectrometry.

BACKGROUND: Serum free light chains (FLCs) are an essential clinical biomarker for the diagnosis and monitoring of patients with plasma cell neoplasms. The current widely used immunoassay methods quantify total serum FLCs, which include monoclonal FLCs as well as FLCs in the polyclonal background. Patients with chronic diseases, inflammatory disorders, or renal dysfunction can have elevated total FLCs that lead to ambiguous results. These patients may benefit from a direct measurement of monoclonal FLCs. The purpose of this study was to develop a method that couples on-probe extraction (OPEX) with liquid chromatography-high-resolution mass spectrometry (LC-HR-MS), abbreviated to OPEX-MS, to directly determine the clonality of FLCs. METHODS: OPEX immunocapture was performed using microprobes loaded with anti-kappa or anti-lambda light chain antibodies. Captured proteins were separated by reversed-phase LC and analyzed by HR-MS. RESULTS: Four cohorts of samples from unique patients were tested based on immunoassay FLC results. The LC-HR-MS analysis in the OPEX-MS method provides both a unique retention time along with deconvoluted masses of FLC monomers and dimers for each clone. The study found that 16 out of 49 (33%) kappa FLC elevated samples as well as 83 out of 100 (83%) dual kappa and lambda FLC elevated samples did not have monoclonal FLCs, which is consistent with the knowledge that there is often no clonal population in samples with mildly elevated FLC immunoassay results. CONCLUSIONS: The OPEX-MS method can serve as a complementary approach to directly determine clonality in patients with difficult-to-interpret FLC immunoassay results.

Clinical and laboratory features of autoimmune hemolytic anemia associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi-AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22-110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2-12.9 g/dL) and 6.3 g/dL (IQR, 6.1-8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi-AIHA were similar in DAT positive and negative patients. ICPi-AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi-AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first-line treatment in the majority of patients with ICPi-AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.

Postibrutinib outcomes in patients with mantle cell lymphoma.

Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval [CI], 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib.

Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck.

The epidermal growth factor receptor (EGFR) is overexpressed in more than 80% of squamous cell cancers of the head and neck (SCCHN). An evolving understanding of the role of EGFR in tumorigenesis has made the receptor an important therapeutic target in SCCHN. Several EGFR inhibitors (EGFRIs) are active in SCCHN, and their use is associated with improvement in progression-free survival and overall survival in various treatment settings. Nevertheless, EGFR inhibition is associated with significant mucocutaneous toxicity that must be balanced against its anticipated efficacy. This review summarizes the relevant clinical trial experience with EGFRIs, with attention to efficacy, toxicity, and methods of selecting patients most likely to benefit from therapy.

Hodgkin Lymphoma: the Changing Role of Radiation Therapy in Early-Stage Disease­the Role of Functional Imaging.

Early-stage classical Hodgkin lymphoma (CHL) is a highly curable malignancy. Historically, extended-field radiotherapy (EFRT) alone showed excellent cure rates, but the risk of radiotherapy (RT)-associated toxicities led to combined modality therapy (CMT) replacing RT alone. RT has subsequently evolved further with significant reductions of dose and field size, and is currently restricted to involved sites only (ISRT). Contemporary CMT yields cure rates in excess of 85%, and most studies do not have adequate follow-up required to evaluate the risk reduction in late effects. In an effort to avoid RT altogether, response-adapted treatment approaches utilizing results of interim [(18)F]fluorodeoxyglucose (FDG) positron emission tomography with fused computed tomography (PET/CT) imaging have been studied. Results from two studies in favorable-risk (UK RAPID and EORTC H10F) and one in unfavorable-risk patients (EORTC H10U) suggest that omission of RT in patients with a negative interim PET/CT response (Deauville score ≤2) yields slightly inferior progression-free survival (PFS) compared to conventional CMT, but with no difference in overall survival (OS) albeit with short-term follow-up. In order to extrapolate results to daily practice, it is critical to understand the selection of patients entered on trials since definitions of favorable and unfavorable disease vary between study groups. Currently, CMT continues to be the standard of care for the vast majority of patients with early-stage CHL and RT is an integral part of therapy in patients with bulky disease. However, for selected patients with favorable characteristics, emerging data suggest that a chemotherapy-alone approach is reasonable.

Bilateral retinal vasculitis associated with cold agglutinin disease treated with obinutuzumab and infliximab.

Purpose: To describe the clinical course and management of a patient with bilateral retinal vasculitis associated with cold agglutinin disease (CAD) treated with obinutuzumab and infliximab. Observations: A 69-year-old Hispanic woman was referred to a tertiary Uveitis Clinic with progressively worsening blurry vision, right eye (OD) worse than left eye (OS). Past ocular history was significant for epiretinal membranes in both eyes (OU). Past medical history was notable for non-specific joint disease, primarily affecting her knees bilaterally, and pulmonary symptoms (e.g., dyspnea, productive cough) of unclear etiologies one year before presentation. She had been evaluated by rheumatologists and pulmonologists and was placed on low doses of prednisone and methotrexate. Upon examination, her visual acuity was 20/40 in OD and 20/25 in OS. Anterior segment exam was unremarkable with no cell or flare in OU. Dilated fundus examination was notable for 0.5+ vitreous haze in OU and mild vessel attenuation in OU. Wide-angle fluorescein angiography (FA) revealed mild bilateral periphery peri-vasculature leakage in OU. Initial blood evaluations revealed decreased hematocrit, and positive anti-nuclear antibody. Her peripheral smear disclosed 3+ agglutination. She was initially treated with mycophenolate mofetil 1000 mg twice daily and prednisone 20 mg then referred to hematology. Further work up revealed high-titer cold agglutinin and positive thermal amplitude screen at 30 °C. Bone marrow examination demonstrated a chronic lymphocytic leukemia (CLL)-like monoclonal B-cell lymphocytosis. Anti-CD20 monoclonal antibody therapy with obinutuzumab was started in an effort to treat the underlying CLL clone and address the associated ocular vasculitis related to CAD. Three months later, after eight cycles of obinutuzumab, the patient's best- corrected visual acuity (BCVA) continued to be stable at 20/30 in OD and 20/20 in OS. However, FA showed persistent diffuse perivascular leakage. Intravenous infliximab with concurrent intravenous methylprednisolone infusions were started. After two cycles of treatment, FA showed significantly improved perivascular leakage. Visual acuity remained stable at 20/25 in OU. Conclusions and importance: Ocular involvement in CAD is rare. The index case is the first report of retinal vasculitis in a patient with CAD. Our report not only describes the unique course of CAD-related retinal vasculitis, but also introduces and underscores a successful therapeutic plan.

Wikipedia: a key tool for global public health promotion.

The Internet has become an important health information resource for patients and the general public. Wikipedia, a collaboratively written Web-based encyclopedia, has become the dominant online reference work. It is usually among the top results of search engine queries, including when medical information is sought. Since April 2004, editors have formed a group called WikiProject Medicine to coordinate and discuss the English-language Wikipedia's medical content. This paper, written by members of the WikiProject Medicine, discusses the intricacies, strengths, and weaknesses of Wikipedia as a source of health information and compares it with other medical wikis. Medical professionals, their societies, patient groups, and institutions can help improve Wikipedia's health-related entries. Several examples of partnerships already show that there is enthusiasm to strengthen Wikipedia's biomedical content. Given its unique global reach, we believe its possibilities for use as a tool for worldwide health promotion are underestimated. We invite the medical community to join in editing Wikipedia, with the goal of providing people with free access to reliable, understandable, and up-to-date health information.

Machine Learning Predictability of Clinical Next Generation Sequencing for Hematologic Malignancies to Guide High-Value Precision Medicine.

Advancing diagnostic testing capabilities such as clinical next generation sequencing methods offer the potential to diagnose, risk stratify, and guide specialized treatment, but must be balanced against the escalating costs of healthcare to identify patient cases most likely to benefit from them. Heme-STAMP (Stanford Actionable Mutation Panel for Hematopoietic and Lymphoid Malignancies) is one such next generation sequencing test. Our objective is to assess how well Heme-STAMP pathological variants can be predicted given electronic health records data available at the time of test ordering. The model demonstrated AUROC 0.74 (95% CI: [0.72, 0.76]) with 99% negative predictive value at 6% specificity. A benchmark for comparison is the prevalence of positive results in the dataset at 58.7%. Identifying patients with very low or very high predicted probabilities of finding actionable mutations (positive result) could guide more precise high-value selection of patient cases to test.

Outcomes after delayed and second autologous stem cell transplant in patients with relapsed multiple myeloma.

We evaluated the outcomes of 168 patients undergoing delayed or second autologous stem cell transplant (ASCT) for relapsed multiple myeloma (MM) from 2010 to 2019. Overall, 21% (n = 35) patients had received a prior transplant and 69% (n = 116) underwent transplant at first relapse. Overall, 27% patients had high-risk cytogenetics and 15% had ISS stage III disease. Stem cell collection was performed after relapse in 72% and 35% of patients received maintenance therapy. Median PFS from salvage treatment and transplant were 28 and 19 months, respectively. Median OS from salvage treatment and transplant was 69 and 55 months. Multivariate analysis revealed that ASCT in first relapse was associated with superior PFS (HR 0.63, p = 0.03) and OS (HR 0.59, p = 0.04) compared to later lines of therapy. In addition, PFS of ≥36 months with prior therapy was associated with improved PFS (HR 0.62, p = 0.04) and OS (HR 0.41, p = 0.01). Ninety-five patients underwent delayed transplant at first relapse, median PFS and OS from start of therapy was 30 and 69 months, and median OS from diagnosis was 106 months. These data may serve as a guide when counseling patients undergoing ASCT for relapsed MM and provide a benchmark in designing clinical trials of transplantation/comparative treatments for relapsed MM.

Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma.

We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.

Splenectomy for benign and malignant hematologic pathology: Modern morbidity, mortality, and long-term outcomes.

BACKGROUND: The role of splenectomy to diagnose and treat hematologic disease continues to evolve. In this single-center retrospective review, we describe modern morbidity, mortality, and long-term outcomes associated with splenectomy for benign and malignant hematologic disorders. METHODS: We analyzed all nontrauma splenectomies performed for benign or malignant hematologic disorders from January 2009 to September 2018. Variables collected included demographics, preexisting comorbidities, laboratory results, intra- and postoperative features, and long-term follow-up. Outcomes of interest included postoperative complications, 30-day mortality, and overall mortality. RESULTS: We identified 161 patients who underwent splenectomy for hematologic disorders. Median age was 54 years (range 19-94), and 83 (52%) were female. Splenectomy was performed for 95 (59%) patients with benign hematologic disorders and for 66 (41%) with malignant conditions. Most splenectomies were laparoscopic (76%), followed by laparoscopic hand assisted (11%), open (8%), and laparoscopic converted to open (6%). Median follow-up was 761 days (interquartile range: 179-2025 days). Major complications occurred in 21 (13%) patients. Three (2%) patients died within 30 days; 16 (9%) died more than 30 days after operation, none from surgical complications, with median time to death of 438 days (interquartile range: 231-1497 days). Among malignant cases, only preoperative thrombocytopenia predicted death (odds ratio = 5.8, 95% confidence interval = 1.1-31.8, P = .04). For benign cases, increasing age was associated with inferior survival (odds ratio = 2.3, 95% confidence interval = 1.0-5.1, P = .05). CONCLUSION: Splenectomy remains an important diagnostic and therapeutic option for patients with benign and malignant hematologic disorders and can be performed with a low complication rate. Despite considerable burden of comorbid disease in these patients, early postoperative mortality was uncommon.

Venetoclax and hypomethylating agent therapy in high risk myelodysplastic syndromes: a retrospective evaluation of a real-world experience.

Treatment with hypomethylating agents (HMAs) azacitidine or decitabine is the current standard of care for high risk myelodysplastic syndromes (MDSs) but is associated with low rates of response. The limited number of treatment options for patients with high risk MDS highlights a need for new therapeutic options. Venetoclax is an inhibitor of the BCL-2 protein which, when combined with an HMA, has shown high response rates in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of high risk MDS patients receiving combination HMA plus venetoclax in order to determine their effectiveness in this context. We show that in our cohort, the combination results in high response rates but is associated with a high frequency of myelosuppression. These data highlight the efficacy of combination HMA plus venetoclax in high risk MDS, warranting further prospective evaluation in clinical trials.

Clinicopathologic characteristics of HER2 FISH-ambiguous breast cancer at a single institution.

BACKGROUND: : The typical algorithm for human epidermal growth factor-2 (HER2) testing is immunohistochemistry (IHC), followed by reflex HER2 fluorescence in situ hybridization (FISH) for HER2 IHC-ambiguous (2+) cases. At our institution, HER2 FISH testing is initially performed as part of routine breast cancer testing, with HER2 FISH-ambiguous (HER2:CEP17 ratio, 1.8 to 2.2) cases reflexed to HER2 IHC. This provides a unique dataset for lesions that may not routinely undergo FISH testing. The clinicopathologic characteristics of HER2 FISH-ambiguous cases are described. DESIGN: : The electronic pathology database in our institution was searched for HER2 FISH-ambiguous cases from 2007 to December 2011. Review of clinical and pathologic characteristics was performed. RESULTS: : Sixty cases from 60 patients were reported as HER2 FISH ambiguous. Reflex HER2 IHC testing was performed on all 60 cases, of which 26 were HER2 IHC negative (0 to 1+), 18 were HER2 IHC ambiguous (2+), and 16 were HER2 IHC positive (3+). Of the 46 HER2 FISH-ambiguous patients with available clinical records, 13 (32%) pursued anti-HER2 treatment (10 IHC 3+, 1 IHC 2+, 2 IHC 0 to 1+). All were grade II or III ductal carcinomas, with 1 grade III metaplastic carcinoma. CONCLUSIONS: : Reflex HER2 IHC testing after initially ambiguous HER2 FISH testing provides definitive HER2 status in a majority of cases (70%). However, a substantial percentage (30%) of HER2 FISH-ambiguous cases is also HER2 IHC ambiguous, suggesting an intermediate HER2 biology. Most HER2 FISH-ambiguous patients who received trastuzumab were HER2 IHC 3+, grade III, and had associated high-grade ductal carcinoma in situ. Although not statistically significant and with only minimal follow-up, no recurrences have occurred in those patients treated with trastuzumab (P=0.5754).