Roxadustat versus placebo for patients with lower-risk myelodysplastic syndrome: MATTERHORN phase 3, double-blind, randomized controlled trial.

In patients with lower-risk myelodysplastic syndromes/neoplasms (MDS), response to first-line therapy is limited and transient. The MATTERHORN randomized, double-blind, phase 3 trial evaluated roxadustat versus placebo for patients with transfusion-dependent, lower-risk MDS. Eligible patients had very low-, low-, or intermediate-risk MDS with or without prior erythropoiesis-stimulating agent treatment, and a transfusion burden of 1-4 packed red blood cell (pRBC) units every 8 weeks (Q8W). Patients were randomized (3:2) to oral roxadustat (2.5 mg/kg) or placebo, both three times weekly, with best supportive care. Primary efficacy endpoint was transfusion independence (TI) for ≥56 days within 28 weeks (TI responders). MATTERHORN was terminated due to interim analysis outcomes not meeting statistical significance. In total, 272 patients were screened, and 140 patients were enrolled (82, roxadustat, and 58, placebo). At final analysis, 38/80 (47.5%) patients and 19/57 (33.3%) in the roxadustat and placebo arms, respectively, were TI responders (p = .217). A greater percentage of patients in the roxadustat arm with a transfusion burden of ≥2 pRBC units Q4W were TI responders (36.1%; 13/36) compared with the placebo arm (11.5%; 3/26; p-nominal = .047). The seven on-study deaths (4, roxadustat, and 3, placebo) were considered unrelated to treatment. Three roxadustat patients progressed to acute myeloid leukemia. Despite MATTERHORN not meeting its primary endpoint, a numerically higher TI rate was achieved with roxadustat treatment compared with placebo. Further analyses are needed to confirm the MDS patient subgroups deriving clinical benefit from this novel treatment.

Open-label, Phase 2 study of roxadustat for the treatment of anemia in patients receiving chemotherapy for non-myeloid malignancies.

Anemia is a common side effect of myelosuppressive chemotherapy; however, chemotherapy-induced anemia (CIA) management options are suboptimal. We evaluated the efficacy and safety of roxadustat in this setting. This open-label Phase 2 study included patients with non-myeloid malignancies and CIA (hemoglobin [Hb] ≤10 g/dL) who had planned concurrent myelosuppressive chemotherapy for ≥8 additional weeks. Oral roxadustat was administered for ≤16 weeks (starting dose 2.0 or 2.5 mg/kg, then titrated every 4 weeks). The primary efficacy endpoint was mean maximum change in Hb within 16 weeks of baseline without red blood cell (RBC) transfusion. Patients were assigned to roxadustat 2.0 (n = 31) or 2.5 mg/kg (n = 61) starting doses, and 89 were assessed for efficacy. The mean (standard deviation) maximum Hb change from baseline without RBC transfusion was 2.4 (1.5) and 2.5 (1.5) g/dL in the roxadustat 2.0 and 2.5 mg/kg groups, respectively. Median (range) time to Hb increase of ≥2 g/dL was 71 (57-92) days. Twelve patients (14.5%) had RBC transfusions (Week 5 to the end of treatment). Roxadustat was efficacious regardless of tumor type and chemotherapy regimen. Deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 14 (15.2%) and nine (9.8%) patients, respectively, and three had serious adverse events attributed to roxadustat in the opinion of the investigators (PE: n = 2 [2.2%]; DVT: n = 1 [1.1%]). Roxadustat increased Hb in patients with CIA regardless of tumor type and chemotherapy regimen. Adverse events were consistent with observations in patients with advanced-stage malignancies.

Roxadustat for the treatment of anemia in patients with lower-risk myelodysplastic syndrome: Open-label, dose-selection, lead-in stage of a phase 3 study.

Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open-label (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase.

Response-adapted therapy with infusional EPOCH chemotherapy plus rituximab in HIV-associated, B-cell non-Hodgkin's lymphoma.

Four cycles of rituximab plus CHOP chemotherapy is as effective as 6 cycles in low-risk diffuse large B-cell lymphoma (DLBCL). Here we report a post-hoc analysis of a prospective clinical trial in patients with HIV-associated DLBCL and high-grade lymphoma treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy. 106 evaluable patients with HIV-associated DLBCL or high-grade CD20-positive non-Hodgkin's lymphoma were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of EPOCH. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by IV bolus cyclophosphamide every 21 days for 4 to 6 cycles. Patients received 2 additional cycles of therapy after documentation of a complete response (CR) by computerized tomography after cycles 2 and 4. 64 of 106 evaluable patients (60%, 95% CI 50%, 70%) had a CR in both treatment arms. The 2-year event-free survival (EFS) rates were similar in the 24 patients with CR who received 4 or fewer EPOCH cycles (78%, 95% confidence intervals [55%, 90%]) due to achieving a CR after 2 cycles, compared with those who received 5-6 cycles of EPOCH (85%, 95% CI 70%, 93%) because a CR was first documented after cycle 4. A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in patients with HIV-associated lymphoma treated with EPOCH plus rituximab, which merits further evaluation in additional prospective trials. Clinical Trials.gov identifier NCT00049036.

Efficacy and safety of ferric carboxymaltose infusion in reducing anemia in patients receiving chemotherapy for nonmyeloid malignancies: A randomized, placebo-controlled study (IRON-CLAD).

Erythropoiesis-stimulating agents (ESA) are effective for chemotherapy-induced anemia (CIA) but associated with serious adverse events. Safer alternatives would be beneficial in this population. The efficacy and safety of ferric carboxymaltose (FCM) as monotherapy for CIA was evaluated. This Phase 3, 18-week, double-blind, placebo-controlled study randomized adults with ≥ 4 weeks of chemotherapy remaining for treatment of nonmyeloid malignancies with CIA to FCM (two 15 mg/kg infusions 7 days apart; maximum dose, 750 mg single/1500 mg total) or placebo. The primary efficacy endpoint was percentage of patients with decreases in hemoglobin (Hb) ≥ 0.5 g/dL from weeks 3 to 18; the key secondary efficacy endpoint was change in Hb from baseline to week 18. Inclusion criteria included: (Hb) 8-11 g/dL, ferritin 100-800 ng/mL, and transferrin saturation (TSAT) ≤35%. In 244 patients (n = 122, both groups), the percent of patients who maintained Hb within 0.5 g/dL of baseline from weeks 3 to 18 was significantly higher with FCM versus placebo (50.8% vs. 35.3%; p = 0.01). Mean change in Hb from baseline to week 18 was similar between FCM and placebo (1.04 vs. 0.87 g/dL) but significantly greater with FCM with baseline Hb ≤ 9.9 g/dL (1.08 vs. 0.42 g/dL; p = 0.01). The percent with ≥ 1 g/dL increase from baseline was significantly higher with FCM versus placebo (71% vs. 54%; p = 0.01), occurring in a median 43 versus 85 days (p = 0.001). Common adverse events in the FCM arm included neutropenia (17%), hypophosphatemia (16%), and fatigue (15%). FCM monotherapy effectively maintained Hb and was well tolerated in CIA.

Changes in the use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in patients with cancer amidst regulatory and reimbursement changes.

PURPOSE: Evaluate changes in use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in cancer patients receiving myelosuppressive chemotherapy following regulatory and reimbursement actions. METHODS: Calendar year patient cohorts (2005-2013) with breast, colorectal, lung, multiple myeloma, non-Hodgkin lymphoma, ovarian, or prostate cancer and receiving myelosuppressive chemotherapy were identified within the Marketscan database. Incidence of ESA treatment and transfusion were estimated in each year, as was median number of ESA administrations. Clinical characteristics associated with ESA administration and transfusions were evaluated by using multivariable logistic regression. Additionally, annual new ESA user cohorts within the Oncology Services Comprehensive Electronic Records database (2011-2014) were examined to assess hemoglobin levels at ESA initiation. RESULTS: Across all tumor types, ESA use decreased substantially (breast cancer: 53.7 to 3.2%; lung cancer: 66.0 to 13.3%, non-Hodgkin lymphoma: 39.8 to 3.8%), transfusion use increased (2 to 5.5%, 5.5 to 18.2%, and 4.5 to 9.1%, respectively), and median number of ESA administrations declined. Across all tumor types, proportion of patients initiating an ESA with hemoglobin >10 g/dL was <10% from 2011 onward. In recent years, cancer patients who are older, female, and have chronic kidney disease or moderate or severe liver disease were most likely to receive ESAs. CONCLUSION: Subsequent to important regulatory and reimbursement ESA-related actions, total ESA exposure among cancer patients receiving myelosuppressive chemotherapy declined substantially. Today, fewer patients receive ESA therapy, and among those treated, more are initiated at hemoglobin levels <10 g/dL and are exposed for a shorter duration, consistent with current product labeling.

Interleukin 1 receptor-associated kinase 1 (IRAK1) mutation is a common, essential driver for Kaposi sarcoma herpesvirus lymphoma.

Primary effusion lymphoma (PEL) is an AIDS-defining cancer. All PELs carry Kaposi sarcoma-associated herpesvirus (KSHV). X chromosome-targeted sequencing of PEL identified 34 common missense mutations in 100% of cases. This included a Phe196Ser change in the interleukin 1 receptor-associated kinase 1 (IRAK1). The mutation was verified in primary PEL exudates. IRAK1 is the binding partner of MyD88, which is mutated in a fraction of Waldenström macroglobulinemia. Together, these two mediate toll-like receptor (TLR) signaling. IRAK1 was constitutively phosphorylated in PEL and required for survival, implicating IRAK1 and TLR signaling as a driver pathway in PEL and as a new drug development target.

Systemically circulating viral and tumor-derived microRNAs in KSHV-associated malignancies.

MicroRNAs (miRNAs) are stable, small non-coding RNAs that modulate many downstream target genes. Recently, circulating miRNAs have been detected in various body fluids and within exosomes, prompting their evaluation as candidate biomarkers of diseases, especially cancer. Kaposi's sarcoma (KS) is the most common AIDS-associated cancer and remains prevalent despite Highly Active Anti-Retroviral Therapy (HAART). KS is caused by KS-associated herpesvirus (KSHV), a gamma herpesvirus also associated with Primary Effusion Lymphoma (PEL). We sought to determine the host and viral circulating miRNAs in plasma, pleural fluid or serum from patients with the KSHV-associated malignancies KS and PEL and from two mouse models of KS. Both KSHV-encoded miRNAs and host miRNAs, including members of the miR-17-92 cluster, were detectable within patient exosomes and circulating miRNA profiles from KSHV mouse models. Further characterization revealed a subset of miRNAs that seemed to be preferentially incorporated into exosomes. Gene ontology analysis of signature exosomal miRNA targets revealed several signaling pathways that are known to be important in KSHV pathogenesis. Functional analysis of endothelial cells exposed to patient-derived exosomes demonstrated enhanced cell migration and IL-6 secretion. This suggests that exosomes derived from KSHV-associated malignancies are functional and contain a distinct subset of miRNAs. These could represent candidate biomarkers of disease and may contribute to the paracrine phenotypes that are a characteristic of KS.

Readmission rates due to venous thromboembolism in cancer patients after abdominopelvic surgery, a retrospective chart review.

PURPOSE: Venous thromboembolism (VTE) is a known cause of morbidity in the oncology patient population. As hospital readmission rates are more frequently scrutinized, we sought to determine the most common causes of 30-day readmissions in the cancer patient following abdominopelvic surgery. Furthermore, due to the high risk of VTE, there have been guidelines established for prophylaxis. As guidelines are based on asymptomatic VTE, we studied the compliance rates of these guidelines in our institution and the rate of symptomatic VTE in the 30-day postoperative period. METHODS: We conducted a retrospective chart review at Pennsylvania Hospital of abdominopelvic surgeries between January 1, 2010 and December 31, 2012 in patients with abdominopelvic malignancies, totaling 263 patients. RESULTS: The median age of our patient population was 67 years and 51.3 % were female. The most common malignancy locations were colorectal (44 %) and pancreas (11 %). One patient did not receive perioperative anticoagulation; most received heparin subcutaneously three times daily, mean duration 5.5 days. Fourteen patients (5 %) received outpatient anticoagulation after discharge; only two had a primary intent of VTE prophylaxis. Thirty-five patients (13 %) were readmitted within 30 days of discharge, the most common reasons being abdominal symptoms and postoperative/surgical complications. There was one patient readmitted for a new, symptomatic VTE. CONCLUSIONS: Our study showed only one new, symptomatic VTE in the study population, despite 95 % of patients not receiving outpatient anticoagulation, which suggests that continued larger and multicenter trials may be needed to study anticoagulation benefits and risks in this patient population.

A phase 1/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy in human immunodeficiency virus-positive patients with cancer: AIDS Malignancy Consortium trial AMC 061.

BACKGROUND: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747). METHODS: In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. RESULTS: Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. CONCLUSIONS: Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir.

Brentuximab vedotin with AVD for stage II-IV HIV-related Hodgkin lymphoma (AMC 085): phase 2 results from an open-label, single arm, multicentre phase 1/2 trial.

BACKGROUND: Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin-AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions. METHODS: We present the phase 2 portion of a multicentre phase 1/2 study. Eligible patients were 18 years or older, had untreated stage II-IV HIV-associated cHL (HIV-cHL), a Karnofsky performance status of more than 30%, a CD4+ T-cell count of 50 cells per µL or more, were required to take ART, and were not on strong CYP3A4 or P-glycoprotein inhibitors. Patients were treated intravenously with 1·2 mg/kg of brentuximab vedotin (recommended phase 2 dose) with standard doses of AVD for six cycles on days 1 and 15 of a 28-day cycle. The primary endpoint of the phase 2 portion was 2-year progression-free survival (PFS), assessed in all eligible participants who began treatment. Accrual has been completed. This trial is registered at ClinicalTrials.gov, NCT01771107. FINDINGS: Between March 8, 2013, and March 7, 2019, 41 patients received study therapy with a median follow up of 29 months (IQR 16-38). 34 (83%) of 41 patients presented with stage III-IV and seven (17%) with stage II unfavourable HIV-cHL. 37 (90%) of 41 patients completed therapy, all 37 of whom achieved complete response. The 2-year PFS was 87% (95% CI 71-94) and the overall survival was 92% (78-97). The most common grade 3 or worse adverse events were peripheral sensory neuropathy (four [10%] of 41 patients), neutropenia (18 [44%]), and febrile neutropenia (five [12%]). One treatment-related death was reported, due to infection. INTERPRETATION: Brentuximab vedotin-AVD was highly active and had a tolerable adverse event rate in HIV-cHL and is an important therapeutic option for people with HIV-cHL. The complete reponse rate is encouraging and is possibly related to a unique aspect of HIV-cHL biology. Upcoming 5-year data will evaluate the sustainability of the outcomes obtained. FUNDING: National Institutes of Health and National Cancer Institute.

Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma.

Rituximab plus intravenous bolus chemotherapy is a standard treatment for immunocompetent patients with B-cell non-Hodgkin lymphoma (NHL). Some studies have suggested that rituximab is associated with excessive toxicity in HIV-associated NHL, and that infusional chemotherapy may be more effective. We performed a randomized phase 2 trial of rituximab (375 mg/m(2)) given either concurrently before each infusional etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) chemotherapy cycle or sequentially (weekly for 6 weeks) after completion of all chemotherapy in HIV-associated NHL. EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by intravenous bolus cyclophosphamide given every 21 days for 4 to 6 cycles. In the concurrent arm, 35 of 48 evaluable patients (73%; 95% confidence interval, 58%-85%) had a complete response. In the sequential arm, 29 of 53 evaluable patients (55%; 95% confidence interval, 41%-68%) had a complete response. The primary efficacy endpoint was met for the concurrent arm only. Toxicity was comparable in the 2 arms, although patients with a baseline CD4 count less than 50/microL had a high infectious death rate in the concurrent arm. We conclude that concurrent rituximab plus infusional EPOCH is an effective regimen for HIV-associated lymphoma.

Thrombocytosis and venous thromboembolism in cancer patients with chemotherapy induced anemia may be related to ESA induced iron restricted erythropoiesis and reversed by administration of IV iron.

ESA therapy can increase hemoglobin, decrease blood transfusions, and improve quality of life in patients with chemotherapy induced anemia (CIA). Despite its benefits, ESA therapy increases the risk of venous thromboembolism (VTE) in cancer patients by 50% and can also cause iron restricted erythropoiesis in CIA patients, which may augment the tendency to develop VTE. We postulated that thrombocytosis, a risk factor for VTE in cancer patients, in CIA patients on ESA therapy might be a result of ESA induced iron restricted erythropoiesis. We performed a retrospective analysis of 187 CIA patients who were randomized to receive weekly Epoetin and IV ferric gluconate, oral ferrous sulfate, or no iron for 8 weeks. Nineteen patients experienced 29 VTEs, and patients, whose platelets increased to ≥350,000 cells/uL were three times more likely to experience a VTE (OR 2.9, P = 0.036, logistic regression) with a four times greater incidence of VTE (IRR 4.4, P = 0.001, Poisson regression). Patients treated with IV iron were significantly less likely to develop platelets of ≥350,000 cells/uL (IRR 0.7, P = 0.013, Poisson regression) and had a decreased incidence of VTE. Our study suggests that ESA associated VTE in CIA patients may be, in part, related to the thrombocytosis of ESA induced iron restricted erythropoiesis and may be countered by IV iron.

Hematologic outcomes and blood utilization in cancer patients with chemotherapy-induced anemia (CIA) pre- and post-national coverage determination (NCD): results from a multicenter chart review.

PURPOSE: In July 2007, the Centers for Medicare and Medicaid Services (CMS) limited coverage of erythropoiesis-stimulating agents (ESAs) in cancer patients with chemotherapy-induced anemia (CIA) through a National Coverage Determination (NCD). The primary objective of this study was to compare transfusion rates in patients with CIA with lung, breast, or colorectal cancer before and after the NCD. METHODS: Adult Medicare patients with CIA treated at 49 community oncology clinics were selected from two time periods based on clinics' NCD implementation date. Chart data were abstracted for 12 weeks post-CIA episode start, defined as hemoglobin (Hb) level <11 g/dL while receiving chemotherapy or within 60 days of the last chemotherapy dose. Multivariate analyses were used to calculate the odds of transfusion and to assess the units of blood transfused, controlling for differences in demographics, clinical history, and chemotherapy. RESULTS: Eight hundred pre-NCD and 994 post-NCD patients from 49 sites were selected. Of the patients, 56% used ESAs post-NCD vs. 88% pre-NCD (p < 0.0001). The duration of ESA use decreased in the post-NCD (32.1 days) vs. pre-NCD (48.4 days, p < 0.0001) group. The post-NCD group reported significantly lower Hb levels, higher odds of receiving a transfusion (odds ratio: 1.41, 95% CI 1.05-1.89, p = 0.0238) and increased blood utilization of 53% (units transfused: OR 1.53, 95% CI 1.15-2.04, p = 0.0034). CONCLUSIONS: Decreased frequency and duration of ESA administration were reported in the post-NCD vs. pre-NCD period. Findings were accompanied by a modest but statistically significant increase in transfusions and a decrease in Hb values.

Lenalidomide and the Expanding Toolkit to Manage Kaposi Sarcoma.

Lenalidomide recently was shown to have clinical activity in patients with human immunodeficiency virus-associated Kaposi sarcoma. Immunomodulatory imine drugs thus provide another tool in the treatment of this challenging neoplasm. See related article by Reid et al., p. 2646.

Risk factors associated with skeletal-related events following discontinuation of denosumab treatment among patients with bone metastases from solid tumors: A real-world machine learning approach.

Background: Clinical practice guidelines recommend the use of bone-targeting agents for preventing skeletal-related events (SREs) among patients with bone metastases from solid tumors. The anti-RANKL monoclonal antibody denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors. However, real-world data are lacking on the impact of individual risk factors for SREs, specifically in the context of denosumab discontinuation. Purpose: We aim to identify risk factors associated with SRE incidence following denosumab discontinuation using a machine learning approach to help profile patients at a higher risk of developing SREs following discontinuation of denosumab treatment. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. Results: A total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19-89) years with a median duration of denosumab treatment of 253 (range, 88-2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer. Conclusion: This analysis showed a higher cumulative number of SREs, prior SREs relative to denosumab initiation, a higher number of hospital visits, and a shorter denosumab treatment duration as significant factors that are associated with an increased SRE risk after discontinuation of denosumab, in both the tumor-agnostic and tumor-specific models. Our machine learning approach to SRE risk factor identification reinforces treatment guidance on the persistent use of denosumab and has the potential to help clinicians better assess a patient's need to continue denosumab treatment and improve patient outcomes.

A retrospective analysis of venous thromboembolism trends in chemotherapy-induced anemia: Red blood cell transfusion versus erythrocyte stimulating agent administration.

Background: Patients receiving a variety of chemotherapy regimens often develop chemotherapy-induced anemia (CIA), which contributes to poor outcomes including increased mortality. Prompt and effective treatment of CIA is essential to prevent fewer chemotherapy dose delays and reductions. Optimal therapy of CIA is controversial and involves the solitary and combined use of intravenous iron, red blood cell (RBC) transfusions, and erythropoietin stimulating agents (ESAs). Despite the baseline coagulopathies present in patients with malignancy, administration of both RBC transfusions and ESAs is associated with venous thromboembolism (VTE). It remains unknown whether the risk of VTE in patients with CIA is greater among patients who receive RBC transfusions or ESAs. Methods: A retrospective study analyzed 10,269 University of Pennsylvania Health System patients with malignancies of various type, stage, and histopathology who developed CIA between 2008 and 2017. Using multivariate Cox regression, we determined adjusted hazard ratios (and corresponding 95% confidence intervals) of VTE development after adjusting for RBC and ESA intervention (all during the 90 days following CIA diagnosis). Results: Among the 10,269 patients with CIA, 2,642 (25.7%) developed a VTE within the 90-day period. VTE risk following RBC transfusion (HR = 1.37, 95% CI 1.24-1.50, P < .001) was more than twice as common as VTE risk following ESA administration (HR = 0.53, 95% CI 0.40-0.69, P < .001). Conclusion: While both RBC transfusion and ESA are independently associated with VTE, our data suggest a greater risk of VTE development with RBC transfusion as compared with ESA.

A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin Alfa for Chemotherapy-Induced Anemia in Patients With Advanced NSCLC.

INTRODUCTION: This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling. METHODS: Adults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 µg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period. RESULTS: The primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR = 0.92; 95% confidence interval [CI]: 0.83‒1.01) and PFS (stratified HR = 0.95; 95% CI: 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio = 0.70; 95% CI: 0.57‒0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed. CONCLUSIONS: Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials.

Health-related quality of life (HRQoL) is a major concern for adults with chronic immune thrombocytopenic purpura (ITP) due to the symptoms associated with the disease and its treatment. This study utilized the ITP-patient assessment questionnaire (ITP-PAQ), a specialized HRQoL questionnaire for ITP, to investigate the humanistic burden of ITP and the impact of romiplostim therapy on HRQoL in two, placebo-controlled, phase 3 clinical trials of splenectomized and non-splenectomized patients. ITP-PAQ was self-administered to ITP patients at baseline, and weeks 4, 12 and 24 of treatment. Splenectomized patients had lower baseline HRQoL scores than non-splenectomized patients in seven of 10 scales (P < 0.05). After 24 weeks of romiplostim therapy, splenectomized patients showed significant improvements over placebo in four of 10 ITP-PAQ Scales (Symptoms, P = 0.0337; Bother, P = 0.0126; Social Activity, P = 0.0145; and Women's Reproductive Health, P = 0.0184). Non-splenectomized patients demonstrated significant improvement over placebo in the Activity Scale (P = 0.0458). Data pooled from the two trials, adjusted for splenectomy status, showed significant improvement for romiplostim-treated patients in six scales; Symptoms, Bother, Activity, Fear, Social Activity and Women's Reproductive Health. These results suggest that adult patients with chronic ITP have improved HRQoL following romiplostim therapy.

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial.

BACKGROUND: Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. METHODS: In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336. FINDINGS: A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected. INTERPRETATION: Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.