Systemic bevacizumab as salvage therapy for persistent severe bleeding and anemia in heyde syndrome following aortic valve replacement.

Heyde syndrome is characterized by the co-occurrence of aortic stenosis and bleeding gastrointestinal angiodysplasias, often with acquired von Willebrand syndrome. Current management for bleeding includes hematologic support with red cell transfusion and intravenous iron and correction of aortic stenosis with valve replacement. However, persistent Heyde syndrome after valve replacement occurs in a significant minority of cases, and there is no accepted therapy for these patients. Given that the pathophysiology of angiodysplasia formation in Heyde syndrome involves dysregulated angiogenesis, targeting angiogenesis may be an effective therapeutic option. We describe two cases of persistent Heyde syndrome with severe bleeding and anemia in patients following aortic valve replacement who were treated with systemic bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor. In both cases, treatment was successful, with resolution of bleeding, liberation from hematologic support, and normalization of hemoglobin. In addition to responding to therapy, neither patient had treatment-related adverse events (and both had recurrent anemia upon treatment discontinuation, further evidence of the therapeutic impact of bevacizumab). Additional investigation into the use of systemic antiangiogenic therapy for treatment of Heyde syndrome is warranted.

Systemic bevacizumab to facilitate anticoagulation in antiphospholipid syndrome and bleeding gastrointestinal angiodysplasia.

Bleeding gastrointestinal angiodysplasia may occur in patients with vasculitis and can be challenging to treat. We describe the novel use of bevacizumab therapy to treat bleeding gastrointestinal angiodysplasia and severe anemia in a patient with eosinophilic granulomatosis with angiitis complicated by antiphospholipid antibody syndrome requiring indefinite warfarin therapy. Studies confirmed multiple bleeding jejunal angiodysplasias unamenable to endoscopic intervention, and the patient required ongoing support with iron infusions and blood transfusions to maintain a minimally acceptable hemoglobin. Given the severe anemia, need for continued, indefinite antiplatelet and anticoagulation therapy, and failure of standard treatment approaches, the patient was initiated on systemic bevacizumab therapy, on the basis of prior documented success of bevacizumab to manage gastrointestinal telangiectasias in patients with hereditary hemorrhagic telangiectasia. Bevacizumab was highly effective, with rapid resolution of bleeding, normalization of hemoglobin, liberation from hematologic support and no adverse events, including no thromboembolic events. Vascular endothelial growth factor (VEGF-A) rose paradoxically after initiation of bevacizumab and normalized after its discontinuation. Given these findings, use of systemic bevacizumab to manage bleeding angiodysplasia in patients with acquired vascular disorders merits further study.

Thrombopoietin level predicts response to treatment with romiplostim in chemotherapy-induced thrombocytopenia.

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of cancer treatment. Evidence has emerged supporting use of romiplostim to treat CIT but predicting clinical response to romiplostim is not possible. To determine utility of endogenous thrombopoietin (TPO) as a biomarker of romiplostim response, we performed an observational cohort study of patients with CIT and known baseline TPO levels receiving romiplostim. For weekly on-romiplostim platelet (Plt) count assessment, clinical response was defined as Plt ≥ 75 × 109 /L and ≥ 30 × 109 /L above pretreatment baseline. Overall, moderate, and superior classes of treatment response were defined based on fraction of Plt assessments meeting clinical response criteria (> 0, ≥ 0.6, and ≥ 0.8, respectively). Sixty-three patients with CIT were included; median age was 62 years, 41.3% were female, and median (IQR) romiplostim treatment duration was 14 (4-38) weeks. Median (IQR) TPO was lower in patients achieving moderate response to romiplostim vs those who did not, 234 (135-1085) pg/mL vs 665 (244-1970) pg/mL (p = .034) and lower still in patients achieving superior response vs those who did not, 212 (91-690) pg/mL versus 559 (173-1851) pg/mL (p = .023). Negative correlations were found between TPO level and baseline Plt and TPO level and response fraction. A positive correlation was found between TPO level and lowest effective romiplostim dose. In receiver operating characteristic (ROC) analysis, optimally discriminant TPO level thresholds (as defined by Youden's Index) were ≤ 457 pg/mL for moderate response and ≤ 260 pg/mL for superior response. In conclusion, TPO levels predict response to romiplostim in CIT, with lower levels predicting improved probability and depth of response.

Characterization of the rate, predictors, and thrombotic complications of thrombocytosis in iron deficiency anemia.

The association of thrombocytosis with iron deficiency anemia (IDA) is well-recognized, but data describing the rate, predictors, and risk of thrombotic complications associated with IDA-related thrombocytosis are limited. We queried an institutional patient data repository containing comprehensive chart data for over 6 million patients to identify IDA patients with and without thrombocytosis and thrombotic events over a 40-year time period (1979 to 2019). Demographics, hematological parameters, thrombosis history, and other medical history were collected. Fidelity of query data was assessed via detailed manual chart review of 700 patients, including confirmation of ferritin and hematologic parameters in addition to temporal and clinical association of thrombocytosis. Our queries identified 36 327 cases of IDA of which 15 022 had thrombocytosis. Following assessment for data integrity, we observed a thrombocytosis rate of 32.6% in patients with IDA. The rate of thrombosis was calculated to be 7.8% in patients with IDA and 15.8% in patients with IDA and thrombocytosis. Platelet mass index at time of peak thrombocytosis was significantly higher than at baseline and was strongly negatively correlated with hemoglobin at peak thrombocytosis. A multivariable model demonstrated a significant predictive relationship between decreasing hemoglobin and increasing platelet count at peak thrombocytosis. In conclusion, we observed reactive thrombocytosis in one-third of IDA patients, and a 2-fold thrombosis risk in patients with IDA and thrombocytosis compared with patients with IDA alone. Given the global burden of untreated and undertreated IDA, adequate IDA treatment may reduce thrombotic complications and associated morbidity and mortality.

Perceptions of Oncologists About Sharing Clinic Notes with Patients.

In a large survey (n = 809) conducted to understand how oncologists differ from nononcologists regarding routinely sharing visit notes with patients, oncologists were less likely to agree patient safety would improve (p = .03) or that patients would be offended after reading notes (p = .01); however, they agreed with nononcologists that sharing notes would lead to less candid documentation (69% vs. 73%; p = .39). Oncologists share a high level of worry about the impact of sharing notes on documentation practices, a concern that will need to be addressed as the practice of sharing visit notes expands to cancer care.

Emerging data on thrombopoietin receptor agonists for management of chemotherapy-induced thrombocytopenia.

INTRODUCTION: Chemotherapy-induced thrombocytopenia (CIT) is a common complication of cancer treatment, frequently leading to reduced relative dose intensity, and is associated with reduced survival. Given the lack of FDA-approved therapies for CIT, thrombopoietin receptor agonists (TPO-RAs) have received significant attention for treatment and prevention of CIT. AREAS COVERED: This review will summarize the development of prior agents for treatment of CIT, discuss the existing literature investigating the use of TPO-RAs in CIT primarily in patients with solid tumor malignancies, and offer insights on the future direction of TPO-RAs and other therapeutics for CIT. EXPERT OPINION: In alignment with NCCN guidelines, we recommend that patients with CIT participate in a clinical trial for consideration of TPO-RA treatment or consider off-label use of romiplostim when participation in clinical trials is not possible. The literature to date supports the use of TPO-RAs for treatment of persistent CIT. Further data is needed to describe the long-term efficacy, safety, and prescribing practices of TPO-RAs in a diverse patient population with a variety of tumor types and chemotherapy regimens in addition to exploring the underlying biology of CIT.

An evaluation of mitapivat for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency.

INTRODUCTION: Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic hemolytic anemia. Until recently, treatment had been limited to supportive management including red blood cell transfusions, splenectomy, and management of chronic disease complications such as iron overload and decreased bone mineral density. AREAS COVERED: We discuss preclinical data and phase 1, 2, and 3 clinical studies evaluating mitapivat for adult patients with hemolytic anemia secondary to PKD. Mitapivat has been shown to offer early and durable improvement in hemoglobin with reduction in transfusion burden, and preliminary data suggest it can induce a negative iron balance in many patients without the use of dedicated iron chelators. EXPERT OPINION: Mitapivat is a first-in-class allosteric activator of pyruvate kinase and the first FDA-approved disease directed therapy for PKD. It has a favorable safety profile and clear clinical efficacy. Given the considerable genetic heterogeneity of PKD and the rapid effect on improving hemoglobin and reducing hemolysis, a therapeutic trial of mitapivat should be considered in all patients with PKD who are not homozygous for the PKLR R479H mutation. Further investigations are needed regarding long-term safety and efficacy profiles and whether long-term PKD-associated complications can be reduced or even reversed.

An updated evaluation of avatrombopag for the treatment of chronic immune thrombocytopenia.

INTRODUCTION: Multiple agents are available for the management of chronic immune thrombocytopenia (ITP), including thrombopoietin-receptor agonists (TPO-RAs), rituximab, and fostamatinib. Although TPO-RAs are often selected as treatments for chronic ITP, when choosing between the TPO-RAs, clinicians must balance safety profile, dosing restrictions, and method of administration incorporating patient preference. AREAS COVERED: We provide an overview of the thrombopoietin receptor agonists with a particular focus on avatrombopag, the newest agent in this class. In phase II and III clinical trials, avatrombopag was shown to offer durable improvement in platelet counts. We also include recent real-world evidence describing avatrombopag effectiveness in patients with poor response to prior treatments (including other TPO-RAs). EXPERT OPINION: Compared with other TPO-RAs used to treat ITP, avatrombopag offers practical oral dosing with a single pill strength, does not require long-term dietary restrictions, and has no warning for hepatotoxicity. It is frequently effective after use of other TPO-RAs in ITP. The primary downside with avatrombopag use at present is the lack of longer-term safety data in ITP that presently exists for romiplostim and eltrombopag.

Systemic bevacizumab for refractory bleeding and transfusion-dependent anemia in Heyde syndrome.

Heyde syndrome, the co-occurrence of aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia, is managed with aortic valve replacement. However, severe bleeding and anemia can preclude safe use of the antiplatelet or anticoagulant therapy required for this intervention. We present a case of the novel and successful treatment of severe, refractory bleeding and transfusion dependence with antiangiogenic therapy in a patient with Heyde syndrome. After systemic bevacizumab was initiated, the patient achieved durable hemostasis with normalization of hemoglobin and liberation from red cell transfusion and dependence on iron infusion; aspirin therapy was successfully initiated where it had previously failed. This durable hemostasis facilitated her subsequent successful transcatheter aortic valve replacement. Plasma vascular endothelial growth factor levels, which were monitored during therapy, paradoxically rose after bevacizumab was initiated but normalized after it was discontinued. Given the angiogenic dysregulation of Heyde syndrome, systemic bevacizumab may be an effective and safe targeted therapy for managing refractory GI bleeding, which thereby facilitates antiplatelet therapy and aortic valve replacement in these challenging cases. Additional investigation into the therapeutic role of inhibiting angiogenesis as a hemostatic modality in Heyde syndrome is warranted.

Direct oral anticoagulants for treatment and prevention of venous thromboembolism in cancer patients.

Venous thromboembolism (VTE) is a common cause of morbidity and mortality in patients with cancer. Compared with the general population, cancer patients with VTE have higher rates of both VTE recurrence and bleeding. While low molecular weight heparin (LMWH) has been the mainstay of treatment for cancer-associated VTE for over a decade, direct oral anticoagulants (DOACs) have recently emerged as a new therapeutic option due to their ease of administration and because they do not require laboratory monitoring. Several large randomized clinical trials have been performed or are ongoing at the time of writing, comparing DOACs with LMWH in this population. Three of these trials have thus far been published and suggest that DOACs are a reasonable alternative to LMWH for management of cancer-associated VTE. Despite the advantages offered by DOACs, these agents may not be appropriate for certain patient groups owing to increased risk of bleeding, organ compromise, extremes of weight, and other issues. Finally, data are emerging suggesting that DOACs may be useful for primary thromboprophylaxis in cancer patients in conjunction with validated risk assessment scores. In this evidence-based review, data for the use of DOACs to treat cancer-associated VTE will be examined, focusing on efficacy, safety, and timing of treatment. Guidance on choosing the optimal anticoagulant for a given patient is also offered.