Karen Carlson

Peripheral Neuropathy with Microtubule-Targeting Agents: Occurrence and Management Approach

Microtubule-targeting agents (MTAs), which include vinca alkaloids, taxanes, and the recently introduced epothilone, ixabepilone, are widely used chemotherapeutic agents for treatment of patients with cancer. MTAs interfere with the normal structure and function of microtubules, leading to cell-cycle arrest and tumor cell death. Microtubule function is critical to normal neuronal function, thus MTA therapy is commonly associated with some form of neuropathy. There is poor agreement between tools for clinical assessment of MTA-associated peripheral neuropathy, and standardization of grading scales is needed to reduce variability. For a majority of patients, MTA-associated neuropathy is mild to moderate in intensity and reversible, but it can be severe and resolve incompletely. The incidence and severity of MTA-associated neuropathy is drug, dose, and schedule dependent. The first-generation vinca alkaloids (eg, vincristine) are associated with severe mixed sensory and motor neuropathy, whereas the newer vinca alkaloids (eg, vinorelbine, vinflunine) induce a milder sensory neuropathy. Taxane-associated sensory neuropathy occurs more often with standard (polyoxyethylated castor oil-based) and albumin-bound paclitaxel than with docetaxel. The incidence and presentation of peripheral neuropathy with ixabepilone, alone or in combination with capecitabine, are similar to that with taxanes. Management of neuropathy may involve reducing or delaying the MTA dose, or in severe persistent or disabling cases discontinuing treatment. Reversal of neuropathy after dosage intervention appears to be more rapid with ixabepilone than with other MTAs.

Decitabine in patients with newly diagnosed and relapsed acute myeloid leukemia.

Abstract Treatment options for older patients with acute myeloid leukemia (AML) and for patients with relapsed/refractory AML are limited, and outcomes are poor. Decitabine, a hypomethylating agent, is active in patients with myelodysplastic syndrome (MDS) and AML, but its optimal dose and schedule are unknown. We report the efficacy and safety of repeated 10-day cycles of decitabine 20 mg/m2 administered intravenously over 1 h in 52 newly diagnosed and 102 relapsed/refractory patients. Repeated 10-day cycles of decitabine produced a complete response (CR) in 40% of newly diagnosed older patients with AML, many of whom had adverse prognostic features. The median overall survival (OS) was 318 days but there was prolonged survival in responders of 481 days. Relapsed/refractory patients had a CR rate of 15.7% with a median OS of 177 days. Extramedullary toxicity was mild and the regimen was well tolerated for ongoing post-remission, outpatient maintenance cycles. Responses were durable for over 1 year.

Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients.

We sought to define the clinical and ultrastructure effects of ixabepilone (Ix), a microtubule‐stabilizing chemotherapy agent on cutaneous sensory nerves and to investigate a potential mitochondrial toxicity mechanism.

Hematological issues in critically ill patients with cancer.

Patients with solid and hematologic malignancies presenting with major bleeding or thrombotic complications, potentially life-ending events in a cancer patients clinical course, usually require admission to an intensive care unit (ICU), making their diagnosis and management even more important for the intensivist. Given the significant advances in the diagnosis and treatment of almost all types of cancers in recent years, the intensivist is likely to encounter an ever-increasing number of cancer patients in the ICU setting with these complications. Abnormal hemostasis can occur as a consequence of both the pathology and treatment of cancer. Because cancer can have multiple effects on hemostatic equilibrium, treatment of these complications can be more complex than in the general population. This article reviews the physiology of coagulation and fibrinolysis, with special attention to those aspects that are most frequently altered in the setting of malignancy. The pathophysiology of bleeding and thrombotic complications specific to critically ill cancer patients are then detailed, and the diagnostic and therapeutic strategies are discussed. Special emphasis is placed on new cancer medications that have an effect on hemostasis, and on novel clotting and anticoagulant agents that are available to the intensivist for the management of these patients.

Risk Factors and Treatment Strategies in Patients With Retinal Vascular Occlusions.

Retinal vein occlusion (RVO) and retinal artery occlusion (RAO) cause significant visual impairment. The role of thrombophilia and cardiovascular testing is uncertain, and optimal treatment strategies have not been determined. We reviewed medical records of 39 patients with RVO and RAO (23 women and 16 men). Thrombophilia and cardiovascular evaluations were performed and outcomes were reviewed. In all, 24 (61.5%) patients had at least 1 thrombophilia. Elevated factor VIII levels were found in RVO (n = 5) but not in RAO. There are no other significant differences in thrombophilias in RVO compared to those in RAO. Most patients had hypertension(41.2% RAO and 55% RVO) and hyperlipidemia (35.5% RAO and 81.8% RVO). In all, 4 women were using oral contraceptives, 2 were pregnant or postpartum. Follow-up data was available for 28 patients (13 RAO, 15 RVO). Nineteen were treated with aspirin, four with warfarin, and one with low molecular weight heparin. Eight patients reported improvement in vision at time of follow-up (5 RAO, 3 RVO). Multiple risk factors are associated with RVO and RAO, and a complete assessment should include thrombophilia and cardiovascular studies.

Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation

Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in randomized trials.

Early Fluorescence in situ Hybridization Assessment during Acute Myeloid Leukemia Induction Chemotherapy

The standard of care for upfront remission induction therapy for “fit” adults with de novo acute myeloid leukemia (AML) is continuous-infusion cytarabine with concurrent anthracycline (i.e., “7+3” regimen) [1]. Fourteen days after the initiation of chemotherapy, bone marrow is re-evaluated to identify patients who may benefit from immediate receipt of an additional cycle of remission induction chemotherapy. Current NCCN guidelines specify that a second cycle of induction chemotherapy should be administered prior to count recovery if (1) more than 5% of the cells in the day-14 bone marrow sample are morphologically consistent with myeloblasts and (2) the clinical status of the patient permits safe administration of cytotoxic therapy [2].

Early Mortality in Patients with Acute Myelogenous Leukemia Treated in Teaching versus Non-teaching Hospitals: A Large Database Analysis

REFERENCES [1] Mistry PK, Belmatoug N, Vom Dahl S, et al. Understanding the natural history of Gaucher disease. Am J Hematol. 2015;90(Suppl 1): S6–11. [2] Zimran A. Velaglucerase alfa: a new option for Gaucher disease treatment. Drugs Today . 2011;47:515–529. [3] Franco M, Collec E, Connes P, et al. Abnormal properties of red blood cells suggest a role in the pathophysiology of Gaucher disease. Blood. 2013;121:546–555. [4] Reihani N, Arlet JB, Dussiot M, et al. Unexpected macrophageindependent dyserythropoiesis in Gaucher disease. Haematologica. 2016;101:1489–1498. [5] Vigan M, Stirnemann J, Caillaud C, et al. Modeling changes in biomarkers in Gaucher disease patients receiving enzyme replacement therapy using a pathophysiological model. Orphanet J Rare Dis . 2014;9:95. [6] Murugesan V, Chuang WL, Liu J, et al. Glucosylsphingosine is a key biomarker of Gaucher disease. Am J Hematol. 2016;91:1082–1089.