LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer.

Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients.

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.

BACKGROUND: Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. METHODS: We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. RESULTS: A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy. CONCLUSIONS: Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).

High rates of durable response are achieved with imatinib after treatment with interferon alpha plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial.

BACKGROUND: Imatinib is the standard of care for newly diagnosed chronic-phase chronic myeloid leukemia. The largest randomized clinical trial of imatinib was the multinational IRIS trial in which 1106 patients were randomized to receive either imatinib 400 mg/day or a standard regimen of interferon-alpha plus cytarabine. DESIGN AND METHODS: Patients were allowed to cross over to the opposite treatment for intolerance, lack of response, disease progression, and, following release of the initial efficacy data, reluctance to remain on therapy with interferon-alpha plus cytarabine. The safety and efficacy of imatinib in patients who crossed over from interferon-alpha plus cytarabine to imatinib is reported here. RESULTS: Of 553 patients originally assigned to interferon-alpha plus cytarabine, 65% crossed over to imatinib, of whom 67% continue to receive treatment. After a median of 54 months of imatinib treatment on study, 93% achieved complete hematologic remission, 86% achieved major cytogenetic remission, and 81% achieved a complete cytogenetic remission as the best observed response. Estimated rates of freedom from progression to accelerated or blast phase and overall survival were 91% and 89%, respectively, at 48 months after starting imatinib. CONCLUSIONS: This is the largest analysis to date describing the efficacy of imatinib in patients who have received prior therapies for chronic myeloid leukemia and it demonstrates excellent responses to this treatment. (ClinicalTrials.gov identifier: NCT00006343).

Invasive anal squamous-cell carcinoma in the HIV-positive patient: outcome in the era of highly active antiretroviral therapy.

INTRODUCTION: The incidence of invasive anal squamous-cell carcinoma in patients with HIV is increasing. We report the outcome after combined chemoradiotherapy for anal squamous-cell carcinoma in HIV-infected individuals. METHODS: Thirty-two HIV-positive patients treated at the St. Vincent's Cancer Care Center for anal squamous-cell carcinoma from 1997 through mid 2005 were reviewed retrospectively. All patients also received highly active antiretroviral therapy. Treatment consisted of radiotherapy concurrent with 5-fluorouracil and mitomycin C in most patients. Overall survival, anal cancer-specific survival, local recurrence, and toxicity were assessed. RESULTS: Median time from completion of radiotherapy to last follow-up of surviving patients was 35 months. Five-year locoregional relapse, anal cancer-specific survival, and overall survival were 16 , 75, and 65 percent, respectively. In multivariate analysis, locoregional recurrence, cancer-specific survival, and overall survival were all significantly associated with tumor size. Overall survival was independently associated with high viral load and low CD4 count. Acute toxicity included: Grade 3 skin in 25 percent of patients, Grade 3 diarrhea: 28 percent, and Grade 3 or 4 hematologic toxicity in 21 and 48 percent, respectively. More than two-thirds of patients required radiotherapy interruption. There was no negative impact of chemoradiotherapy on viral load. CONCLUSIONS: Outcome after chemoradiotherapy for HIV-related anal squamous-cell carcinoma in the era of highly active antiretroviral therapy is comparable to outcome in patients without HIV. However, significant toxicity is seen with standard treatment regimens. Earlier diagnosis and risk-adapted therapy could lead to improved survival and decreased treatment-related morbidity.

Communicating about chemotherapy-induced anemia.

Many validated instruments exist for determining the impact of chemotherapy-induced anemia and related fatigue on patient quality of life, but few studies analyze how healthcare providers actually discuss these subjects with patients. The authors share their study results on patterns of communication between participating patients and their physicians and allied health professionals. Letters of invitation were mailed to over 1,000 community-based oncologists, 15 of whom met the criteria and agreed to participate in this study on a first-enrolled basis until sufficient participation was ensured. In total, 36 of their patients were audio- and/or video-recorded during their regularly scheduled visits. Post-visit interviews were conducted separately with patients and participating healthcare professionals. Interviews were transcribed and analyzed using sociolinguistic techniques. Although 52% of visit time was spent discussing side effects and symptoms, most discussions of anemia and fatigue lacked specificity necessary to determine their true impact on patients' lives. Physician inquiries regarding fatigue also tended to be too brief to elicit patients' chief concerns. Vocabulary used to discuss anemia and related fatigue was variable and imprecise, and no fatigue assessment instrument was used or referenced in any visit. Community-based oncologists are encouraged to modify their vocabulary and consider incorporating a validated fatigue instrument, either within or before the consultation, to improve the quality of such communication.

Randomized comparison of epoetin alfa (40,000 U weekly) and darbepoetin alfa (200 microg every 2 weeks) in anemic patients with cancer receiving chemotherapy.

This is the first randomized, open-label, multicenter trial designed and powered to directly compare the hemoglobin (Hb) response to epoetin alfa (EPO), 40,000 U once weekly (QW), with that to darbepoetin alfa (DARB), 200 microg every 2 weeks (Q2W), in anemic patients with cancer receiving chemotherapy (CT). Transfusion requirements, quality of life (QOL), and safety also were evaluated. Adults with solid tumors scheduled to receive CT for > or =12 weeks and with baseline Hb < or =11 g/dl were randomized to receive either EPO 40,000 U QW (n = 178) or DARB 200 microg Q2W (n = 180) s.c. for up to 16 weeks. Doses were increased for nonresponders (Hb increase <1 g/dl) after 4 (EPO) or 6 (DARB) weeks, as per National Comprehensive Cancer Network guidelines, and were reduced for a rapid rise in Hb (>1.3 g/dl [EPO] or >1.0 g/dl [DARB] within any 2-week period) or for an Hb level >13 g/dl. The proportion of patients achieving a > or =1-g/dl Hb rise by week 5, the primary end point, was significantly higher with EPO (47.0%) than with DARB (32.5%), and EPO-treated patients achieved a > or =1-g/dl Hb increase significantly earlier than those receiving DARB (median, 35 days versus 46 days). The mean increase in Hb from baseline was significantly higher at weeks 5, 9, 13, and the end of the study with EPO than with DARB. The number of units transfused per patient was significantly lower for the EPO group than for the DARB group. The proportions of patients requiring transfusions, mean QOL improvements, and tolerability profiles were similar in the two groups.

Assessing the clinical benefits of erythropoietic agents using area under the hemoglobin change curve.

INTRODUCTION: In assessing erythropoietic agents for chemotherapy-induced anemia, traditional single time-point end points (e.g., hematopoietic response [HR]) fail to reflect clinical benefits over the entire therapy course. Area under the hemoglobin change curve (Hb AUC) is introduced as an alternative measure, and its reliability, clinical significance, and superiority are assessed. METHODS: Using data from a phase IV open-label epoetin alfa (EPO) trial, we tested Hb AUC reliability by comparing its values derived from primary patient data with those derived from aggregated data. Clinical significance of the Hb AUC was investigated in three phase IV EPO trials by examining the linear relationship between Hb AUC quartiles and established clinical end points. The superiority of the Hb AUC over HR in its association with blood transfusion was tested through logistic regressions and area under the receiver operating characteristic (ROC) curve analysis. RESULTS: The Hb AUC values derived from patient and aggregated data were similar. Strong and statistically significant linear trends of decreasing transfusion requirements, increasing quality-of-life improvements, and decreasing time to HR were found across Hb AUC quartiles. The Hb AUC rendered the HR variable insignificant when both were present in the same model. Area under the ROC curve analysis supported the superior performance of the Hb AUC. CONCLUSIONS: We found that the Hb AUC is an objective, reliable, clinically meaningful, and comprehensive summary statistic that may be used to quantify clinical benefits for patients receiving erythropoietic agents. Further prospective validation of the Hb AUC metric is recommended.

A pilot study to evaluate the safety and clinical outcomes of once-weekly epoetin alfa 80,000 u in anemic patients with cancer receiving chemotherapy.

BACKGROUND: Epoetin alfa is indicated for the treatment of chemotherapy-induced anemia at doses of 150 U/kg 3 times weekly or 40,000 U once weekly. Higher starting doses may lead to higher hematologic response rates (RRs), earlier hematologic responses, and earlier identification of nonresponders. The hematologic response and safety of epoetin alfa at a starting dose of 80,000 U once weekly in anemic patients (hemoglobin [Hb] 13 g/dL or increased > 1.3 g/dL in a 2-week period during the 12-week study. The primary efficacy endpoint was major hematologic response (Hb increase >/= 2 g/dL or Hb >/=12 g/dL, independent of transfusion). Secondary endpoints were minor hematologic response (Hb increase >/= 1 g/dL but > 2 g/dL) and incidence of transfusions. RESULTS: Of 69 patients enrolled, 47 (68%) completed the study. A majority of patients (72%) exhibited a major hematologic response with epoetin alfa 80,000 U once weekly. Mean Hb levels increased by 2.2 g/dL from baseline after 12 weeks of therapy. Six patients (8.8%) received packed red blood cell transfusions during the study. The dose of epoetin alfa was reduced, or held then reduced, per protocol in 48 patients (69.6%). Ten patients (14.5%) in the safety population experienced a total of 11 clinically relevant thrombotic vascular events. CONCLUSION: Epoetin alfa at a starting dose of 80,000 U once weekly (with appropriate dose reductions) increased Hb level, was associated with a packed red blood cell transfusion rate > 5% after 4 weeks of therapy, and was safe and generally well tolerated in anemic patients with cancer receiving chemotherapy. The hematologic RR, however, was not markedly improved compared with previous trials with 40,000-60,000 U once weekly, perhaps partly because of the high frequency of dose reductions.

Managing hematologic toxicities.

This overview of the hematologic toxicities of cancer chemotherapy addresses the frequency and clinical significance of neutropenia, anemia, and thrombocytopenia and attempts to provide evidence-based guidelines, based on clinical trials, for the use of cytokine growth factors and transfusion support. The current emphasis on high-dose and dose-dense chemotherapy increases the need for close attention to the amelioration ofhematologic toxicities. The latter is highly dependent upon the appropriate and judicious use of cytokine support. Although these supportive agents may be relatively nontoxic, it is important to understand their potential side effects and to use them only when warranted by evidence-based studies.

Treatment of chemotherapy-related anemia with erythropoietic agents: current approaches and new paradigms.

Anemia is common among patients with cancer receiving chemotherapy (CT) and/or radiotherapy (RT) and may limit cancer treatment, clinical outcomes, and overall patient quality of life (QOL). In the United States, epoetin alfa and darbepoetin alfa are approved for the treatment of CT-induced anemia in patients with nonmyeloid malignancies. Goals of treatment are to reduce transfusions, increase hemoglobin (Hb) levels, and improve overall QOL. Results from ongoing head-to-head trials comparing these agents will allow for direct comparisons of Hb response profiles and overall QOL effects. To optimize patient benefits from erythropoietic therapy, new doses and schedules of these agents are being studied. Data from investigations of the use of a higher weekly starting dose ("front-loading") followed by maintenance dosing on a less frequent schedule (when Hb has increased to a specified level or by a specified amount after the higher initial starting dose) suggest that both agents can increase and subsequently maintain Hb levels on such schedules. This approach may lead to benefits for patients and healthcare providers, such as earlier increases in Hb and earlier identification of nonresponders. Consequently, evolving strategies with erythropoietic agents should ultimately improve overall QOL in anemic cancer patients receiving CT.