Hypoalbuminemia is significantly associated with increased clearance time of high dose methotrexate in patients being treated for lymphoma or leukemia.

As a weak acid, methotrexate (MTX) is bound to serum albumin and has variable protein binding. The purpose of this study was to assess serum albumin's relationship with MTX pharmacokinetics by comparing MTX clearance and toxicities between patients with normal serum albumin to those with hypoalbuminemia. This single-center retrospective study included adult patients with leukemia or lymphoma who received their first MTX at a dose ≥1 g/m2. Hypoalbuminemia was defined as serum albumin ≤3.4 g/dL. MTX clearance was defined as the first documented time the MTX level ≤0.05 µM. Fisher's exact tests and Wilcoxon rank sum tests were used to examine differences in toxicities, and Cox proportional hazard regression was used to assess relationship with time to clearance. Of 523 patients identified, 167 patients were evaluable. One hundred thirty-five patients had normal serum albumin and 32 had hypoalbuminemia. Hypoalbuminemia was associated with a higher proportion of patients experiencing edema, ascites or pleural effusions (34 vs. 12 %, p = 0.006), and the concomitant use of nephrotoxic agents (41 vs. 20 %, p = 0.021). Hypoalbuminemia was associated with a significantly longer time to MTX clearance (median 96 vs. 72 h, p = 0.004). In addition, patients with hypoalbuminemia had a higher proportion of hyperbilirubinemia and significantly longer hospitalization (median 14 vs. 5 days, p < 0.001). In conclusion, hypoalbuminemia was associated with increased time to MTX clearance and increased length of hospitalization. High dose MTX is safe to administer in patients with low albumin levels, with appropriate leucovorin rescue, and good supportive care.

Intensified Mycophenolate Mofetil Dosing and Higher Mycophenolic Acid Trough Levels Reduce Severe Acute Graft-versus-Host Disease after Double-Unit Cord Blood Transplantation.

Although mycophenolate mofetil (MMF) has replaced corticosteroids as immunosuppression in cord blood transplantation (CBT), optimal MMF dosing has yet to be established. We intensified MMF dosing from every 12 to every 8 hours to augment graft-versus-host disease (GVHD) prophylaxis in double-unit cord blood transplantation (dCBT) and evaluated outcomes according to the total daily MMF dose/kg in 174 dCBT recipients (median age, 39 years; range, 1 to 71) who underwent transplantation for hematologic malignancies. Recipients of an MMF dose ≤ the median (36 mg/kg/day) had an increased day 100 grade III and IV acute GVHD (aGVHD) incidence compared with patients who received >36 mg/kg/day (24% versus 8%, P = .008). Recipients of ≤ the median dose who had highly HLA allele (1 to 3 of 6) mismatched dominant units had the highest day 100 grade III and IV aGVHD incidence of 37% (P = .009). This finding was confirmed in multivariate analysis (P = .053). In 83 patients evaluated for mycophenolic acid (MPA) troughs, those with a mean week 1 and 2 trough < .5 µg/mL had an increased day 100 grade III and IV aGVHD of 26% versus 9% (P = .063), and those who received a low total daily MMF dose and had a low mean week 1 and 2 MPA trough had a 40% incidence (P = .008). Higher MMF dosing or MPA troughs had no impact on engraftment after myeloablation. This analysis supports intensified MMF dosing in milligram per kilogram per day and MPA trough level monitoring early after transplantation in dCBT recipients.

Current treatment landscape and emerging therapies for metastatic triple-negative breast cancer.

A lack of therapeutically targetable molecular alterations and its aggressive nature make triple-negative breast cancer (TNBC) a challenging disease. Chemotherapy is standard of care for most patients with metastatic disease, but median overall survival is less than 18 months. Unravelling the molecular underpinnings of TNBC revealed it to be a potentially highly immunogenic subtype within a more broadly immunologically inert cancer type, suggesting that it may respond to immunotherapy. An urgent need for new therapies is being filled in part by recent successes with immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor 1 and programmed death ligand 1 (PD-L1). Although single-agent ICIs had limited activity, exploration of rational combinations has yielded 2 new FDA approvals for atezolizumab and pembrolizumab in combination with chemotherapy, leading to a new standard of care for patients with PD-L1-positive disease. Two FDA-approved companion diagnostic PD-L1 assays are available to identify patients eligible for immunotherapy treatment, but other biomarkers of response are also being examined. Ongoing clinical trials are also evaluating a range of targeted therapies as combination partners, which may have immunomodulatory effects in addition to their main mechanism of action, complementing the activity of ICIs. This article will evaluate the current and emerging clinical trends in the use of ICIs as part of combination regimens in the treatment of patients with metastatic TNBC.

Current treatment landscape and emerging therapies for pancreatic cancer.

Pancreatic cancer remains a disease that is difficult to treat due to a typically late presentation, relatively high resistance to chemotherapy, and lack of effective targeted therapies. The standard of care relies on cytotoxic chemotherapy, primarily FOLFIRINOX and gemcitabine-based regimens. Dose modifications and/or the use of alternative combinations can reduce adverse effects, but these regimens remain highly toxic. As a result, long-term survival is low for patients with advanced or metastatic disease. There is a great need for novel anticancer agents that provide efficacy with minimal toxicity. Currently, inhibitors of immune tolerance and immune checkpoint inhibitors; PARP inhibitors; novel cytotoxic chemotherapies, such as trifluridine/tipiracil; and modifiers of the tumor microenvironment, such as pegylated hyaluronidase, are in clinical trials for the treatment of pancreatic cancer. This activity will review the current treatment landscape and preview emerging therapies for the treatment of advanced pancreatic cancer.

Similar incidence of typhlitis in patients receiving various doses of daunorubicin or idarubicin as induction for acute myeloid leukemia.

BACKGROUND: The current standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) is an anthracycline plus cytarabine. Both anthracyclines and cytarabine have been associated with the development of typhlitis, a serious adverse event characterized by inflammation of the bowel wall in patients with profound neutropenia, diagnosed by abdominal CT imaging and clinical symptoms. Given the paucity of available data, the aim of our study was to determine the incidence of typhlitis among AML patients receiving induction chemotherapy with idarubicin 12 mg/m2 (IDA), daunorubicin 60 mg/m2 (DNA60), or daunorubicin 90 mg/m2 (DNA90). METHODS: Adult patients with AML or MDS receiving either daunorubicin or idarubicin along with cytarabine as part of their induction regimen between January 1, 2009 and June 30, 2013 were included. A definition of typhlitis required CT confirmation of inflammation of the cecum only, defined as non-tumoral bowel wall thickening with or without pericolonic fat infiltration and fluid, according to CTCAE version 4.03 along with clinical symptoms. The primary endpoint was to determine the incidence of typhlitis among IDA, DNA60, and DNA90. Secondary endpoints included characterizing the variability of doses used in induction therapy and identifying any potential risk factors for the development of typhlitis. RESULTS: The overall incidence of typhlitis was 2.5%. When the definition was broadened to include the colitis, enteritis, or enterocolitis, the incidence increased. The inter-reliability ratings of the 2 radiologists' evaluations for each definition indicated substantial agreement (0.803 cecum, 0.834 ileocecal region only, and 0.752 enterocolitis). Neither the anthracycline chosen, nor the dose had a statistically significant impact on the incidence of typhlitis. In patients that developed typhlitis, all patients had clinical symptoms in addition to documented cecum inflammation on CT scan. All patients were managed conservatively with intravenous broad-spectrum antibiotics. CONCLUSION: To our knowledge, this is the first study to compare the incidence of typhlitis in adult patients receiving idarubicin or daunorubicin for the treatment of AML. The cumulative incidence of typhlitis was similar to the currently published literature, with the incidence being similar irrespective of the anthracycline chosen or dose. All patients were managed conservatively with broad-spectrum antibiotics. A more definitive definition of typhlitis may help clinicians identify affected patients sooner and choose appropriate targeted therapy.

Overview of chemotherapy-induced nausea and vomiting and evidence-based therapies.

Among patients with cancer, chemotherapy-induced nausea and vomiting (CINV) is a common adverse effect that not only impacts quality of life, but also treatment outcomes. It is important to address these issues from both prevention and treatment standpoints so that patients remain adherent to their regimens. With CINV being classified into 5 different types, the primary medication options for prevention and treatment include 5-HT3 receptor antagonists, NK1 receptor antagonists, and corticosteroids. Other medications used, but to a lesser extent, include dopamine antagonists, benzodiazepines, cannabinoids, and olanzapine. In addition, those patients who express interest in alternative or nonpharmacologic therapies may have options as well. With the array of medications available for patients with cancer, pharmacists play an integral role in optimizing patient outcomes. Therefore, it is important that pharmacists stay up-to-date on the most current guidelines available for CINV treatment.

Upfront use of plerixafor and granulocyte-colony stimulating factor (GCSF) for stem cell mobilization in patients with multiple myeloma: efficacy and analysis of risk factors associated with poor stem cell collection efficiency.

Plerixafor (P), an agent that selectively and reversibly binds to the chemokine receptor CXCR4, has been approved in combination with G-CSF (P + G-CSF) for stem cell (SC) mobilization in patients with multiple myeloma (MM). The goal of this study was to determine the SC collection success rate of P + G-CSF using a clinically relevant outcome defined as the ability to collect at least 5 × 106 CD34+ cells/kg to allow safely two transplants, and identify risk factors impacting SC mobilization. One hundred and thirty-eight patients were mobilized with P + G-CSF upfront following induction. The SC collection success rate was 92.8%. We identified exposure to lenalidomide alone (p = .038), WBC count <4 × 103/mcL prior to mobilization (p = .01) and non-African American race (p = .019), as risk factors for low efficiency by multivariate analysis. This study demonstrates that P + G-CSF is highly efficient in MM patients and provides strong support for its upfront use in SC collection for MM patients.

Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center.

PURPOSE: Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF). PATIENTS AND METHODS: We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival. RESULTS: Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids. CONCLUSION: IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.

Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death.

We hypothesized that the high early death rate (EDR) due to bleeding in acute promyelocytic leukemia (APL) is in part attributable to delays in all- trans retinoic acid (ATRA). We conducted a retrospective analysis of the timing of ATRA administration. 204 consecutive patients with newly diagnosed APL between 1992 and 2009 were identified. The EDR was 11%. 44% of early deaths occurred in the first week. Hemorrhage accounted for 61% of early deaths. ATRA was ordered the day APL was suspected in 31% of patients. Delays in ATRA administration led to increases in the percentage of early deaths from hemorrhage.

High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis.

PURPOSE: This study was designed to determine the incidence of venous and arterial thromboembolic events (TEEs) in patients treated with cisplatin-based chemotherapy and to analyze the prognostic value of patients' baseline and treatment characteristics in predicting TEE occurrence. PATIENTS AND METHODS: We performed a large retrospective analysis of all patients treated with cisplatin-based chemotherapy for any type of malignancy at Memorial Sloan-Kettering Cancer Center in 2008. A TEE was cisplatin-associated if it occurred between the time of the first dose of cisplatin and 4 weeks after the last dose. RESULTS: Among 932 patients, 169 (18.1%) experienced a TEE during treatment or within 4 weeks of the last dose. TEEs included deep vein thrombosis (DVT) alone in 49.7%, pulmonary embolus (PE) alone in 25.4%, DVT plus PE in 13.6%, arterial TEE alone in 8.3%, or DVT plus arterial TEE in 3.0%. TEEs occurred within 100 days of initiation of treatment in 88% of patients. By univariate analysis, sex, age, race, Karnofsky performance status (KPS), exposure to erythropoiesis-stimulating agents, presence of central venous catheter (CVC), site of cancer, stage of cancer, leukocyte and hemoglobin levels, and Khorana score were all identified as risk factors. However, by multivariate analysis, only age, KPS, presence of CVC, and Khorana score retained significance. CONCLUSION: This large retrospective analysis confirms the unacceptable incidence of TEEs in patients receiving cisplatin-based chemotherapy. In view of the controversy associated with prophylactic anticoagulation in patients with cancer treated with chemotherapy, randomized studies are urgently needed in this specific cancer population treated with cisplatin-based regimens.

Modification of vincristine dosing during concomitant azole therapy in adult acute lymphoblastic leukemia patients.

OBJECTIVE: Vincristine is an important component in the treatment of acute lymphoblastic leukemia (ALL) and is now the backbone of therapy in the induction and consolidation phases of this disease. Proper dosing of vincristine is required to maximize disease control while avoiding toxicity. The gastrointestinal toxicity of vincristine such as decreased peristalsis can potentially be increased if the CYP 3A4 enzyme is inhibited. This interaction may become more prevalent with increasing use of CYP 3A4 inhibitors such as the azole antifungals. Since azoles are increasingly being used for prophylaxis and treatment of fungal infections in this patient population, an assessment of vincristine dosing and toxicity is the first step to constructing guidelines for the coadministration of these agents. METHODS: ALL patients !18 years of age receiving vincristine-based therapy from August 2003 through December 2007 with or without azole therapy were included. Data was collected using electronic patient medical records and the pharmacy system (RxTFC). Information was entered into a database for this retrospective study. Patients were separated into two arms; vincristine with azoles and vincristine only. Patient demographic information, chemotherapy regimen, vincristine-induced symptoms, and concurrent strong CYP 3A4 inhibitors and inducers were collected. RESULTS: A total of 50 patients received vincristine of which 29 (58%) had concurrent azole therapy. No patients received concurrent major CYP 3A4 inhibitors and the baseline characteristics were similar between groups. Vincristine dosing modifications were more common in the azole group (58.6 vs. 23.8%; p = 0.02). The mean dose reduction of vincristine when combined with an azole was 46.5%. Symptoms of decreased peristalsis were more common in patients receiving azoles (65.5 vs. 28.6%; p = 0.019) and on average occurred after the second vincristine dose. Symptoms occurred in 50, 75, and 66.6% of patients receiving fluconazole, voriconazole, and posaconazole, respectively. Patients were more likely to have an incomplete course of vincristine when receiving azole therapy (48.3 vs. 9.5%; p = 0.004). CONCLUSION: Caution should be used with the coadministration of vincristine and azoles. It is recommended that institutional guidelines be developed to standardize care for patients receiving vincristine with azole therapy. Potential measures to avoid this interaction include revisiting azole prophylaxis in this patient group and being judicious in azole selection.