Krishna Gundabolu

Venous thromboembolism in patients with hematologic malignancy and thrombocytopenia

The optimal management of hematologic malignancy‐associated venous thromboembolism (VTE) in patients with moderate‐to‐severe thrombocytopenia is unclear. This is a retrospective study of 128 adult patients with hematologic malignancies who were diagnosed with VTE. The outcome of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Forty‐seven patients (36.7%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 10,000/µL (range 2,000–45,000/µL) versus 165,000/µL (50,000–429,000/µL) in those without (P < 0.001). The median duration of significant thrombocytopenia in the first group was 10 days (1–35 days). Therapy during the period of significant thrombocytopenia included prophylactic‐dose low‐molecular‐weight heparin (LMWH) (47%), therapeutic‐dose LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%), and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At a median follow‐up of more than 2 years, the risk of clinically significant bleeding (11% vs 6%, P = 0.22) including major bleeding (6% vs 2%) and clot progression or recurrence (21% vs 22%, P = 1.00) were similar in patients with or without significant thrombocytopenia. In a multivariate analysis, the risk of recurrence/progression (hazard ratio, HR 0.59, 95% CI 0.21–1.66, P = 0.31) and hemorrhage rate (HR 0.29, 95% CI 0.05–1.56, P = 0.15) did not differ based on the presence of significant thrombocytopenia. Within the limits of this retrospective study, cautious use of prophylactic‐dose LMWH may be safe in thrombocytopenic patients with hematologic malignancy‐associated VTE. Am. J. Hematol. 91:E468–E472, 2016.

Early Mortality and Overall Survival of Acute Myeloid Leukemia Based on Facility Type

Cancer health disparities may exist based on the facility type. We aimed to determine the association between the academic status of centers and outcomes of patients with acute myeloid leukemia (AML). Using the National Cancer Data Base, we compared 1‐month mortality and long‐term overall survival (OS) of 60 738 patients with AML, who received first course treatment between 2003 and 2011 at academic or nonacademic centers (community cancer program, comprehensive community cancer program, and others). Multivariate analysis was done using logistic regression for one‐month mortality and Cox regression with backward elimination approach for OS. Patients treated at academic centers differed from those at nonacademic centers in that they were younger with a median age of 62 versus 70 years (P < .0001), more often an ethnic minority (P < .0001), had lower education level (P = .005), lower co‐morbidity score (P < .0001), a different income (P < .0001), and insurance profile (P < .0001), and more often received chemotherapy (P < .0001) and transplant (P < .0001). Receipt of care at nonacademic centers was associated with worse 1‐month mortality (29% vs. 16%, P < .0001) and 5‐year OS (15% vs. 25%; P < .0001). After adjusting for prognostic covariates, the 1‐month mortality (odds ratio, 1.52; 95% confidence interval, CI 1.46‐1.59; P < .0001) and OS were significantly worse in nonacademic centers, compared to academic centers. Our large database study suggests that the receipt of initial therapy at academic centers is associated with lower 1‐month mortality and higher long‐term OS. Investigation of the underlying reasons may allow reducing this disparity.

Reduced-intensity conditioning allogeneic hematopoietic-cell transplantation for older patients with acute myeloid leukemia

Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials.

Reversal of Anticoagulation and Management of Bleeding in Patients on Anticoagulants.

Bleeding is the most common complication of all anticoagulants. Any bleeding patient on an anticoagulant should be risk-stratified based on hemodynamic instability, source of bleeding, and degree of blood loss. Although minor bleed may be managed with discontinuation of anticoagulant, major bleed may require transfusion of blood products and use of specific antidote. The residual effects of each anticoagulant may be monitored with distinct coagulation assay. Intravenous or oral vitamin K can reverse the effect of warfarin within 24 to 48 hours and is indicated for any bleeding, international normalized ratio of >10 or 4.5 to 10 in patients with other risk factors for bleeding. Fresh frozen plasma or prothrombin complex concentrate (PCC) may be necessary in major bleeding related to warfarin. Protamine sulfate reverses the effect of unfractionated heparin completely and of low-molecular-weight heparin (LMWH) partially. Idarucizumab has recently been approved in United States for dabigatran reversal, whereas andexanet alfa is expected to get approved in the near future for reversal of oral factor Xa inhibitors. The PCC may reverse the effect of rivaroxaban to some extent, but no data are available regarding reversal of apixaban and edoxaban. Aripazine has shown promising results to reverse the effects of LMWH, fondaparinux, and direct oral anticoagulants but is still in the developmental phase.

Initial therapy for acute myeloid leukemia in older patients: principles of care

Abstract Older patients with acute myeloid leukemia (AML) frequently have significant comorbidities, geriatric syndromes, and high-risk leukemia that make them susceptible to high early mortality, chemotherapy-related toxicities, and poor long-term survival. The receipt of chemotherapy or hematopoietic cell transplantation is low, and the choices between intensive or low-intensity chemotherapy is often not clear. Geriatric and multidisciplinary interventions targeted to optimize functional status and improve management of comorbidities may enhance chemotherapy tolerance. Comprehensive geriatric assessment, and other integrated risk assessment models have been developed to predict the risk of chemotherapy-related toxicities and survival, and may guide therapy assignment. Development of low intensity but effective therapy is a major need. Deeper understanding of the molecular biology of AML has allowed several novel therapies to enter clinical trials in recent years. Continuation of successful collaboration between several stakeholders will be necessary to build upon the clinical and research improvements made thus far.

Utilization of initial chemotherapy for newly diagnosed acute myeloid leukemia in the United States

The use of chemotherapy in patients with acute myeloid leukemia (AML) is associated with survival benefits and alleviation of symptoms related to AML. Prior studies have demonstrated a lower receipt of chemotherapy with increasing age and comorbidities. We hypothesized that socioeconomic and health system factors also determine the use of chemotherapy. We included 61 775 adults with AML diagnosed between 2003 and 2011 from the National Cancer Database, and performed a multivariable logistic regression model to determine the association between receipt of chemotherapy and several factors. A total of 15 608 patients (25.3%) did not receive chemotherapy. In a multivariable analysis, the likelihood of getting chemotherapy declined with increasing age and comorbidities and among patients with therapy-related and intermediate-/high-risk AML. Other factors associated with a lower likelihood of receiving chemotherapy included receipt of care in nonacademic centers, African American race, lower income status, uninsured or Medicare insurance status, and female sex. Compared with the previous studies, our study is novel because it provides data from a large, unselected cohort of patients diagnosed in the United States in recent years, and simultaneously examines the effect of various biological, socioeconomic, and health system factors. The results of our study raise a possibility of leukemia care disparity based on socioeconomic and health system factors. Better understanding of ways such factors may influence receipt of chemotherapy may allow an increase in the use of chemotherapy.

An Algorithmic Approach to Management of Venous Thromboembolism

Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Factors such as the presence of transient risk factors for VTE, risk of bleeding, and location of deep vein thrombosis (DVT) determine the duration of anticoagulation. Extended anticoagulation is offered to patients with unprovoked pulmonary embolism (PE) or proximal DVT and a low risk of bleeding. Anticoagulation for 3 months is advised in patients with provoked DVT or PE, high risk of bleeding, and isolated distal or upper extremity DVT. In patients with unprovoked PE or proximal DVT and a low risk of bleeding, who want to stop anticoagulation after 3 months, further risk stratification is necessary. Clinical scoring system, and thrombophilia testing otherwise not routinely performed, may be considered to measure risk of annual recurrence in such cases. Short-term anticoagulation may be considered in subsegmental PE and superficial vein thrombosis, particularly if patients are at low risk of bleeding and have persistent risk factors for recurrent VTE. In cases of catheter-associated thrombosis, the catheter need not be removed routinely, and the patient may be anticoagulated for 3 months or longer if the catheter is maintained in patients with cancer. Extensive screening for occult cancer in cases of unprovoked VTE is not beneficial. New oral anticoagulants such as apixaban, rivaroxaban, or dabigatran may be preferred to vitamin K antagonists in patients without cancer or renal failure, more so after the development of reversal agents such as idarucizumab and andexanet alfa.