Gerald A Soff

Chemotherapy-induced thrombocytopenia (CIT) is a challenging and common complication of cytotoxic chemotherapy in patients with GI cancers. There is no widely available approved treatment. Avatrombopag is a potent, second-generation oral thrombopoietin receptor agonist promising for CIT management. We conducted a multicenter, randomized, double-blind, investigator-initiated US trial of avatrombopag or placebo (1:1) in GI cancer patients with persistent CIT (platelets ≤85 × 10 /L on day 1 of a chemotherapy cycle despite adequate time to recover from the prior cycle). The primary end point was successful correction of CIT and prevention of recurrence (defined as recovery of platelets to ≥100 × 10 /L, no chemotherapy dose modification/delay, and prevention of CIT recurrence [platelets ≥100 × 109/L] at end of the on-study cycle). The trial was closed to enrollment by the data and safety monitoring board at the planned interim analysis after meeting prespecified stopping criteria for efficacy. Sixteen of 23 patients (70% [95% CI, 47 to 87]) receiving avatrombopag achieved the primary end point versus 4/24 patients (17% [95% CI, 5 to 37]) receiving placebo ( = 3.67, < .001). The median (IQR) platelet count at the end of the on-cycle treatment period was 157 (136-202) × 10 /L with avatrombopag versus 72 (68-134) × 10 /L with placebo. Adverse events (AEs) and serious AEs occurred in 78% and 17% of patients receiving avatrombopag and 46% and 0% of patients receiving placebo, respectively. No serious AEs were study drug-related. There were no treatment-related AEs leading to death or discontinuation of study drug. In this randomized, placebo-controlled trial, avatrombopag was efficacious in the management of persistent CIT in patients with GI cancers. These findings are promising for a common, challenging oncologic complication that prevents delivery of full-dose, on-time, cancer-directed therapy.

Current guidelines recommend consideration of prophylactic anticoagulation in lymphoma, supported by the Khorana score, which assigns lymphoma 1 point for risk of developing venous thromboembolism (VTE). We hypothesized that different lymphoma types convey different risk of VTE. To better characterize VTE rates and predictive parameters, we assessed lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) events in 879 lymphoma patients. VTE was found in 4.9%, with a higher incidence rate among patients with aggressive lymphoma (8.3%), compared with indolent lymphoma (1.9%) and Hodgkin lymphoma (0%). The International Prognostic Index (IPI) was a strong predictor of VTE. The Khorana score did not predict VTE within lymphoma but was and independent risk factor for mortality. VTE was also an independent risk factor for mortality. Our study confirms that lymphoma subtypes are associated with different VTE risks.

COVID-19 is associated with increased mortality and morbidity. The mortality and adverse outcomes of current era COVID-19 variants have not been comprehensively studied. To evaluate the association between COVID-19 variants and vaccination status on venous thromboembolism (VTE) and mortality rates, especially among recent strains, compared to a control group with acute respiratory infection (ARI). A retrospective cohort study was conducted using the N3C database. Inclusion criteria were adult patients with COVID-19 or ARI between 3/1/2020-11/1/2024. Cohorts were balanced on demographics, prior healthcare visits, prior anticoagulation/antiplatelet use, COVID-19 vaccination and comorbidities. Primary outcomes were 30-day VTE and mortality using multivariable regression analysis. Kaplan Meier survival curves were used to determine the duration of post-infectious VTE and mortality risk. A total of 756,217 patients with COVID-19 and 678,747 with ARI were included. Patients with COVID-19 had an increased risk of VTE (OR: 1.45) and mortality (OR: 1.80) compared to the ARI cohort. However, risk was attenuated later in the pandemic, with similar risk between patients with COVID-19 and ARI in the Contemporary Omicron period (May 2022-Dec 2024), especially among vaccinated individuals. Vaccination was associated with a reduced odds of VTE (OR: 0.41) and mortality (OR: 0.41). The post-COVID elevated VTE and mortality risk plateaued after 8 weeks. COVID-19 was associated with increased risk of 30-day VTE and mortality compared to ARI, but was no longer significantly different during the contemporary period (2022-2024) of the pandemic. COVID-19 vaccination was associated with reduced VTE events and mortality. 1.COVID-19 is associated with increased mortality and thrombosis2.Using a large national database, we studied COVID-19 30-day mortality and thrombosis3.Current era (2022-2024) COVID-19 was not more severe than acute respiratory infection4.COVID vaccination reduced thrombosis and mortality rates by approximately 60%

Background/Objectives: Intensive chemotherapy is the cornerstone of lymphoma treatment but often leads to severe chemotherapy-induced thrombocytopenia (sCIT), resulting in treatment delays, reduced dose intensity, and the need for transfusions. While granulocyte colony-stimulating factors (G-CSFs) are commonly used to manage neutropenia, the use of thrombopoietic growth factors has not been adequately studied. Methods: This phase I dose-finding study evaluated the use of weekly romiplostim as prophylaxis for recurrent sCIT in patients undergoing chemotherapy for lymphoma. Eligible patients were those treated with a 21-day chemotherapy cycle who previously experienced sCIT, thus serving as their own “controls”. sCIT was defined as one of the following: (A) a platelet count (PLT) <50 × 109/L on day 1 of the subsequent cycle, leading to delay or dose reduction in chemotherapy, or (B) grade 4 thrombocytopenia (<25 × 109/L) and/or (C) platelet transfusion for bleeding. The primary endpoints were the incidence of sCIT and the rate of romiplostim-associated-adverse-events, with thromboembolic complications being an event of special interest. Results: Nine patients with sCIT requiring a PLT transfusion on the prior treatment cycle were treated across three dose schedules. The phase 2 recommended schedule was defined as a starting dose of 3–5 mcg/kg based on the baseline PLT count, with weekly adjustments for counts <150 × 109/L and >450 × 109/L. Romiplostim prevented recurrent grade 4 thrombocytopenia in 47% of the chemotherapy cycles and averted recurrent transfusion in 65% of cycles. Notably, low starting doses, as used in solid malignancies, were insufficient, leading to recurrent thrombocytopenia. Conclusions: Romiplostim was well-tolerated, with no thromboembolic events, and allowed most patients to complete their chemotherapy on schedule at full dose intensity.

Hematopoietic growth factors (HGFs) and their receptors play essential roles in regulating hematopoiesis. While several HGFs and cytokines have been identified and characterized, three HGFs have had marked impacts on clinical medicine. We will discuss the clinical uses and unique side-effect profiles of erythropoietin, granulocyte colony-stimulating factor, and thrombopoietin mimetics along with current clinical implications of granulocyte-macrophage colony-stimulating factor and Interleukin-1 in this comprehensive chapter.

Background: The diagnostic approach for patients with hemolytic anemia, typically involves assessment of an immune versus non-immune mechanism, i.e. direct antiglobulin test (DAT) for IgG and/or C3d. Management then is directed to the underlying etiology, whether IgG, IgM/complement, or non-immune mechanism. We present a very rare case where this approach did not apply: pure IgA-mediated hemolytic anemia, with consistently negative DAT for IgG and C3d. Case Presentation: A 39-year-old woman, with no past history of anemia, developed severe anemia over 3 months. At an outside hospital, her hemoglobin (Hgb) levels had been as low as 5.9 gm/dL, requiring transfusion of approximately 30 units of packed red cells in the prior 3 months. Bone marrow biopsy showed mild dyserythropoiesis, marked erythroid hyperplasia, and normal iron stores. No diagnosis was made, and she received no treatment except transfusions. She was transferred to our hospital for hematology consult. At our initial visit, laboratory findings were indicative of hemolytic anemia. Absolute reticulocyte count was 0.26 X 10^9/L (Nl: 0.02-0.08), with her reticulocyte percent as high as 46.0% (Nl: 0.5-2.0%). Haptoglobin was <10 mg/dL (Nl: 43-212), LDH 1,186 U/L (Nl: 100-200). Total bilirubin was modestly elevated, 2.1 mg/dL (Nl 0.2-1.2 mg/dL), predominantly unconjugated. DAT was repeatedly negative for IgG and C3d. Fluorescein-labeled proaerolysin (FLAER), Donath-Landsteiner testing, and eosin-5'-maleimide test for were all negative. Hemoglobin electrophoresis was normal. Genetic panel (37 genes) for hereditary hemolytic anemia was unrevealing. Aggressive hemolysis persisted requiring 5 red cell transfusions in 2 weeks. Notably, multiple specimens sent for peripheral smear review were rejected by the lab due to “Specimen unsuitable for testing due to hemolysis.” Ultimately, peripheral smear was obtained and revealed anisopoikilocytosis, marked polychromasia, and red cell agglutination. The Soluble C5B-9 (SC5B-9) complex level was markedly elevated (>1200 pg/mL, Nl < 250) Based on the agglutination and SC5B-9 complex level, she received two weekly doses of sutimlimab, without impact on her anemia or hemolysis markers. In the absence of an identified etiology for the critical hemolytic anemia, we reconsidered the possibility of an immune-mediated process. An extended DAT was obtained (VERSITI reference lab). The results were weakly positive for polyspecific DAT, negative for IgG, C3b, C3d, but strongly positive (4+) for IgA. We therefore arrived at the diagnosis of pure IgA-mediated, immune hemolytic anemia. The patient received a course of dexamethasone IV 40 mg X 4 days and IVIG 1 gram/Kg, daily X2. Within 2 weeks of the dexamethasone/IVIG, the patient's Hgb increased from 7.8 gm/dL to 12.0 gm/dL, the LDH declined from 1523 to 284 and the SC5B-9 normalized. She was transitioned to prednisone at discharge, and the dose was gradually tapered to 20 mg daily, without relapse 10 months later. Conclusions: Educational Points: “When you have eliminated all which is impossible, then whatever remains, however improbable, must be the truth,” per Sherlock Holmes, in The Sign of Four, Sir Arthur Conan Doyle. This case illustrates a true diagnostic dilemma, as the standard approach to the diagnosis of severe, life-threatening hemolytic anemia was unrevealing. It was only when we considered an improbable etiology, i.e. pure IgA-mediated immune hemolytic anemia, despite repeated negative DAT, did we identify the diagnosis. The true incidence of pure IgA-mediated immune hemolytic anemia is unknown, as the diagnosis is not easy to make, but is extremely rare. In one study of 5235 patients with immune hemolytic anemia, over a 14-year period, 124 patients had IgA antibodies to red cells detected. However, only 6 had IgA without concomitant IgG or IgM. (Sokol, RJ. e al. Transfusion 1997). Those 6 patients had C3d present and 3 also had C3c. Only one other case of Pure IgA-mediated hemolytic anemia, without C3d, has been reported. (Chadebech P et al, Blood 2010). In this case, complement activation was believed to be the mediator of hemolysis. And while sutimlimab did not resolve the hemolysis, glucocorticoids and IVIG rapidly resolved the hemolysis, without relapse.

Background: Monoclonal Gammopathy (MG)-related coagulopathies have been described in several case reports and small series involving multiple myeloma and other lymphoplasmacytic/plasma cell dyscrasia disorders and occur from a variety of mechanisms. To our knowledge, there are no systematic evaluations of the frequency, clinical associations, and underlying mechanisms of paraprotein induced coagulopathy in a cohort of patients with such disorders. Methods: We reviewed the 3,657 patients diagnosed with a MG over a ten-year period (5/2015-5/2025) at a single academic cancer center. Cases included MG of undetermined significance (MGUS), smoldering (SMM) and multiple myeloma (MM), AL amyloidosis, lymphoplasmacytic lymphoma (LPL), and marginal zone/splenic B-cell lymphoma. Cases were screened for elevated PT/INR (INR>1.3) and/or aPTT (>38.0) at presentation, and/or had a coagulation factor assay performed. This resulted in a total of 599 cases for detailed review. Results: Fifteen cases (0.41% of total cohort) had a coagulopathy that was attributable to the MG. Of these cases, coagulopathies were found in 6 patients with MM, 4 with MGUS, 2 with AL amyloidosis, 1 with LPL, 1 with splenic B-cell lymphoma, and 1 with marginal zone lymphoma. Four of the 15 cases presented with overt bleeding, which included muscle hematoma (n=2), hematochezia (n=1), and oral bleeding (n=1). The remaining 11 cases were diagnosed through abnormal coagulation laboratory analysis without overt bleeding. Nine of the cases had factor deficiency (von Willebrand Disease: n=4, factor X: n=4, factor VIII: n=1). Four had antiphospholipid antibody syndrome (APS), one had a direct thrombin inhibitor, and one had a mixed pattern (factor VIII deficiency and APS). Three of the factor X deficiency cases were in the context of known, or clinically suspected AL amyloidosis, while one patient with MM had a strong factor X inhibitor and no evidence of AL amyloidosis. Two-thirds of the cases had a kappa light-chain MG (n=10), consistent with the typical proportion in MG patients. Among the 11 cases with a heavy chain immunoglobulin component, IgM elevation occurred in 6 cases, and IgG in 5. Interestingly, all 4 of the APS cases were IgM (2 kappa and 2 lambda). The mean monoclonal protein level among cases with quantifiable spikes (n=11) was 1.48 g/dL. The majority of cases (n=10) underwent treatment for the underlying hematologic disorder. Half of the treated patients experienced a complete resolution of the coagulopathy (n=5), 2 cases demonstrated a partial improvement, and 3 cases had persistent coagulopathy despite treatment. No deaths were attributed to coagulopathy in these patients. Conclusions: To our knowledge, this is the first systematic evaluation of MG-related coagulopathies across a large population of lymphoid/plasmocytic neoplasms. Also unique to our study is the description of coagulopathy outcomes following treatment. Our findings reveal a spectrum of coagulation targets with implications for diagnosis and therapeutic decision-making.Treatment of the underlying disorder resulted in complete or partial improvement of the coagulopathy in most but not all cases. There was no specific pattern of IgG verus IGM, or kappa versus lambda light chain. Early recognition and consideration of treatment may prevent bleeding complications and improve coagulopathy in similar cases.

•All lung cancer types have comparable risks of VTE, and within lung cancer, the KS did not add to VTE risk prediction.•The overall KS and the individual hematologic parameters are associated with overall survival in lung cancer. [Display omitted] Venous thromboembolism (VTE) is a frequent complication in patients with lung cancer, but the risk factors and incidence in different lung cancer subtypes have not been fully characterized. Despite multiple studies supporting the use of VTE prophylaxis in patients with cancer at increased risk of VTE based on the Khorana score (KS), routine use of VTE prophylaxis is uncommon in clinical practice. This study further characterizes the risk factors and incidence of VTE in patients with lung cancer at a university cancer center. Furthermore, we assessed the association of KS and its individual components with overall survival in this same group of patients. Using natural language processing and human review to detect thrombotic events in the electronic medical record, a 12-month incidence of 10.1% was identified in the 632 patients with lung cancer analyzed. Significant risk factors included age <60 years and white blood cell (WBC) count ≥11 × 109/L, but KS itself was not significantly associated with VTE. The median overall survival was 12 months with VTE. The KS, age ≥60 years, stage III to IV, WBC count ≥11 × 109/L, hemoglobin <10 g/dL, body mass index, surgery, and VTE were identified as significant predictors of death. These findings warrant further validation, because the KS and 2 of its individual components in this study of lung cancer were significantly associated with reduced overall survival.