Non-infectious Pneumonitis Research Articles

Updated Results of a Phase I Study of RAD001 In Combination with Lenalidomide In Patients with Relapsed or Refractory Multiple Myeloma with Pharmacodynamic and Pharmacokinetic Analysis

AbstractAbstract 3051 Background:Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. RAD001, an mTOR inhibitor has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Informed by our previous studies demonstrating synergistic anti-MM activity of mTOR inhibitors when combined with Len, we studied this combination to evaluate its safety and activity as a non-steroid containing oral regimen in advanced MM. Methods:Patients with relapsed and refractory MM were assigned to Len and RAD001 to be taken for 21 days of a 28 day cycle (NCT00729638) in a standard 3+3 design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity and were required to receive concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Peripheral blood and bone marrow samples were collected before and after treatment for pharmacokinetic and pharmacodynamic studies. Results:Twenty-eight patients were registered on the trial between December 2008-December 2009. Two patients were inevaluable because of either rapidly progressive disease or failure to meet eligibility criteria on day 1. Data on 26 patients are therefore available. Pts had received a median of 4 prior lines of treatment.14 pts had received Len previously of which 11 pts had relapsed disease and 3 pts had relapsed/refractory disease. Both cohort 1 (Len: 10mg/day and RAD001: 5mg/every other day ×21 days of 28 day cycle) and 2 (Len: 15mg/day and RAD001: 5mg daily ×21 days of 28 day cycle) required expansion because of grade 3 neutropenia and grade 4 thrombocytopenia. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg × 21 days). The maximum tolerated dose (MTD) was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Most common (≥10%) Grade 1/2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which proved manageable with supportive care. One patient developed RAD related non-infectious pneumonitis requiring therapy discontinuation. Grade 3/4 adverse events (≥ 5%) included thrombocytopenia (11%) and neutropenia (22%). Nineteen patients completed 2 cycles and were evaluable for response. Median follow up is currently 8.7 months and median PFS is 4.3 months, with 12 patients receiving treatment at MTD. Overall response rate was 68% (13/19) (90% CI: [30-76%]) including CR(1) PR(2), MR(8) and SD(2). Four patients continue on the combination at 13, 14, 15 and 17 months respectively.Pharmacokinetic and pharmacodynamic data including immunohistochemistry for phosphorylated AKT, cytokine profiles, T cell subsets and transcription profile on MM cell pre and post treatment as well as correlation of response with pharmacodynamic studies will be presented. Conclusions:The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population with advanced MM. This combination thus provides an oral steroid free combination treatment strategy which warrants future evaluation in phase II studies. Disclosures:Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Adams:Novartis: Employment. Makrides:Celgene: Employment. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Raje:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Astra Zeneca: Research Funding; Acetylon: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide and RAD 001 for treatment of relapsed and refractory multiple myeloma.

Phase I study of the oral mammalian target of rapamycin inhibitor everolimus (RAD001) in Japanese patients with relapsed or refractory non-Hodgkin lymphoma

Phase I study was conducted to evaluate the safety, pharmacokinetics (PK) and efficacy of the oral mammalian target of rapamycin inhibitor, everolimus (RAD001), in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Patients received everolimus 5 or 10mg orally once daily. Dose escalation was based on the safety assessment and the probability of dose-limiting toxicities (DLTs) using a Bayesian logistic model. DLTs were evaluated in six patients at each dose level during the initial 28days of study treatment. A total of 13 patients were enrolled; 5mg (seven) and 10mg (six). No DLTs were observed at either dose level. Frequently observed potentially drug-related adverse events included leukopenia (8/13), thrombocytopenia (8/13), elevated hepatic transaminase (9/13), stomatitis (7/13), anemia (6/13), and nasopharyngitis (6/13). All adverse events were reversible. Non-infectious pneumonitis (grade 1) in one patient resolved following discontinuation of everolimus. Two patients with diffuse large B cell lymphoma and two patients with follicular lymphomas achieved objective responses with an overall response rate of 31% (4/13). The pharmacokinetic profiles were not different from those in non-Japanese patients. Everolimus was well tolerated at doses up to 10mg/day and showed potential efficacy in relapsed or refractory NHL, warranting further investigation.

Results of a phase I study of RAD001 in combination with lenalidomide in patients with relapsed or refractory multiple myeloma.

8032 Background: Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (MM) patients following ≥1 prior therapy. RAD001, an mTOR inhibitor has been studied as a single agent in MM and had no significant single-agent activity, but was well tolerated. Predicated upon our previous preclinical studies demonstrating synergistic anti-MM activity of mTOR inhibitors when combined with Len, we evaluated this combination as a non-steroid containing oral regimen in advanced MM. Methods: Patients (pts) with relapsed and refractory MM were assigned to Len and RAD001 to be taken for 21 days of a 28 day cycle (NCT00729638). Pts were allowed to continue therapy until disease progression or unacceptable toxicity. Results: Twenty-eight pts were registered on the trial;2 pts were replaced for rapidly progressive disease or failure to meet eligibility criteria on day 1. Data on 26 pts are currently available. Both cohort 1 and 2 required expansion because of grade 3 neutropenia and grade 4 thrombocytopenia. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 pts in cohort 3 (Len: 20 mg and RAD001: 5 mg × 21 days). The maximum tolerated dose (MTD) was therefore declared at 15 mg of Len and 5 mg of RAD001 for 21 days with a 7 day rest period. Most common (≥10%) grade 1/2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. One pt developed RAD related non-infectious pneumonitis requiring discontinuation of therapy. Grade 3/4 adverse events ≥ 5% included thrombocytopenia (11%) and neutropenia (22%). Nineteen pts completed 2 cycles and are evaluable for response: 12 pts received treatment at MTD. Overall response rate including MR + PR was 63% (90% CI: [30.76%]), with 1 pt achieving SD. Conclusions: The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. The response rate to date has been encouraging in this heavily pretreated pt population. This combination provides an oral, steroid-sparing treatment strategy which warrants future evaluation in phase II studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Celgene, Millennium, Novartis Celgene, Millennium, Novartis AstraZeneca, Millennium, Novartis

Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib

Everolimus (RAD001, Afinitor((R)) Novartis) is the first oral inhibitor of mTOR (mammalian target of rapamycin) to reach the oncology clinic. Everolimus 10 mg daily achieves complete inhibition of its target at below the maximum tolerable dose for most patients. A phase III randomized placebo-controlled trial has examined the impact of everolimus in patients with clear cell renal cancers and progressive disease on or within 6 months of the VEGFR tyrosine kinase inhibitors sunitinib and/or sorafenib. The primary endpoint of progression-free survival was increased from median 1.9 to 4.9 months (hazard ratio 0.33, P < 0.001) and 25% were still progression-free after 10 months of everolimus therapy. There was a delay in time to decline of performance status and trends to improvement in quality of life, disease-related symptoms, and overall survival despite crossover of the majority of patients assigned to placebo. In 2009, everolimus was approved in the US and Europe as the only validated option for this indication. Toxicities are usually mild to moderate and can be managed with dose reduction or interruption if necessary. Opportunistic infections and non-infectious pneumonitis are seen as a class effect. Management of common practical management issues are discussed. Clinical trials are in progress to examine additional roles for everolimus in renal cancer, alone and in combination with other agents.

Noninfectious Pneumonitis after Everolimus Therapy for Advanced Renal Cell Carcinoma

Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors. To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus. Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis. Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%). Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124).

Obstructive pneumonitis in lung cancer patients--a retrospective study

We evaluated the frequency and the backgrounds of lung cancer patients with obstructive pneumonitis. Among 84 cases of lung cancer, 35 presented with bronchial obstruction at bronchoscopy or on radiological studies. Of these 35 cases, 8 had infectious obstructive pneumonitis. This complication was observed more commonly in patients with squamous cell carcinoma. A comparative analysis of the immunological and nutritional states before the occurrence of bacterial complication was performed on patients with infectious obstructive pneumonitis and those with non-infectious obstructive pneumonitis. The serum concentration of total protein, albumin and total cholesterol was significantly lower in patients who subsequently developed bronchial obstruction and bacterial infection, compared to concentrations in patients with non-infectious obstructive pneumonitis. Similarly, there was significant decrease in the number of peripheral lymphocytes, and neutrophils as well as a significant reduction of the serum concentration of IgM in the group of patients with infectious complications. These results suggest that nutritional and immunological deficiencies, in association with local airway obstruction, may be determining factors in the occurrence of infectious obstructive pneumonitis in patients with lung cancer.

Non-Infectious Pneumonitis (NIP) in Breast Cancer (BC) Patients (Pts) Treated with Everolimus (Afinitor™) Containing Therapy: Analysis of Five Studies.

Abstract Background: Everolimus (E), an oral mTOR inhibitor, has been and is currently being evaluated in combination with antitumor therapies for the treatment of BC. NIP is an infrequent but serious adverse event (AE) observed with mTOR inhibitors; NIP pathogenesis has not been clearly established. This analysis provides a descriptive summary of this AE in the BC trials reported with E to date. Materials and Methods: Overall 269 pts were treated with E-containing therapy in 5 BC studies (Table). In most pts, NIP was diagnosed and monitored by CT imaging and pulmonary function tests (spirometry, DLCO, room air O2 saturation at rest). Management guidelines based on worst grade (G) were implemented since phase 1 protocols and include: G1 no specific therapy required and continue treatment at full dose; G2/G3 short course of corticosteroids and hold and/or reduce E until improvement to ≤G1; G4 discontinuation of the treatment. Results: Few cases of NIP (2.9%) were reported in a phase 2 study of neoadjuvant E combined with letrozole for 4-months, in which chest assessments were not routinely requested (Baselga, J Clin Oncol, 2009). All 3 cases of NIP that were reported as severe AEs were resolved within 15 days of E discontinuation. In metastatic BC pretreated pts, E has been investigated in a NCI-C CTG phase 2 study (Ellard, J Clin Oncol, in press). In this study an overall NIP rate of 41% was reported, and was the reason for therapy discontinuation in 5 pts (10%). Most cases (35%) were G1 or G2, with subtle radiological changes (patchy ground-glass changes over the lung parenchyma) in the absence of clinical symptoms, or with a rapid resolution of symptoms and findings after dose reduction/treatment suspension, or corticosteroid use. In all cases, resolution of NIP occurred. In HER2+ heavily pretreated metastatic BC pts, the combination of E, trastuzumab, and paclitaxel or vinorelbine, has been investigated in 2 phase 1 studies (n=64) (O'Regan, SABCS 2008; Fasolo, SABCS 2008). Per protocols, these patients were regularly assessed with chest CT scans or X-rays every 8-9 weeks and received corticosteroids, anti-histamines, and H-2 antagonists as premedication. NIP at the time of the analysis was observed in 1 case: the pt developed a G3 event after 6 cycles and permanently discontinued treatment. After prednisolone treatment, the pt recovered within 13 days. Conclusion: NIP is an infrequent and manageable event in pts with BC treated with E alone or in combination regimens. Routine radiological screening of the chest can ensure early detection and appropriate management of this AE. Non-infectious pneumonitis n (%)AuthorStudy PhaseBC SettingN*RegimenG1/G2G3Baselga, 2009Ph 2, randomizedEstrogen receptor+neoadjuvant138E 10mg/d + L for 16 wks1 (0.7%)3 (2.2%)Ellard, 2009Ph 2, randomizedMetastatic49E 10mg/d or 70mg/wk17 (35%)3 (6%)Awada, 2008Ph 1bMetastatic18E 5-10mg/d + L00O'Regan, SABCS 2008Ph 1bHER2+ metastatic27E 5-10 mg/d or 30mg/wk + H + P01 (3.7%)Fasolo, SABCS 2008Ph 1bHER2+ metastatic37E 5mg/d or 20-30mg/wk + H + V00H, trastuzumab 2 mg/kg weekly; L, letrozole 2.5mg daily; P, paclitaxel 80 mg/m² Day 1, 8, 15 q4w; V, vinorelbine 25 mg/m² Day 1, 8 q3w. *N = patients treated with E-containing therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1115.

Introduction: Infection in Solid Organ Transplant Recipients

Infectious disease after transplantation remains a field in evolution. Improved immunosuppressive therapies for organ transplantation have reduced the incidence of allograft rejection while increasing susceptibility to opportunistic infections and virally mediated malignancies. Traditional patterns of opportunistic infection after transplantation have also been altered by the emergence of organisms with antimicrobial resistance and by antifungal (including Pneumocystis) and antiviral prophylaxis (i.e. for cytomegalovirus [CMV] and other herpesviruses) (1). Improved microbiologic diagnostic tools (e.g. nucleic acid testing) are used in the routine management of common infections (e.g. CMV, Epstein-Barr virus [EBV]) and have allowed the definition of new clinical syndromes (e.g. BK polyomavirus nephropathy) and of donor-derived infections (e.g. due to lymphocytic choriomeningitis virus [LCMV]). At the same time, a variety of newer techniques are available, largely on a research basis (e.g. HLA-linked tetramer binding, intracellular cytokine staining) to assess pathogen-specific immunity. These may be used to investigate the recipient’s susceptibility to specific infections and are increasingly entering clinical practice. In the past decade, Transplant infectious disease has emerged as an integral subspecialty component of most successful transplant programs.

Pomalidomide (CC4047) Plus Low Dose Dexamethasone (Pom/dex) Is Active and Well Tolerated in Lenalidomide Refractory Multiple Myeloma (MM).

Abstract 429 Background:Patients with MM who have progressed after multiple novel agents have limited treatment options. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent that has demonstrated response rates of 63% in a Phase 2 trial of Pom/dex in patients with relapsed MM (in press, JCO). To better define the response rate in this group, we treated an additional cohort of patients who were truly resistant/refractory to lenalidomide. Methods:To be eligible, patients must:be refractory to lenalidomide therapy defined as relapsing on or within 60 days of stopping lenalidomide. Pomalidomide was given orally 2 mg daily on days 1–28 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1, 8, 15 and 22 of each cycle. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily as prophylaxis against DVT. Pom/dex regimen would be declared promising if we observed at least 4 confirmed responses out of 34 patients based on a single stage Fleming design. Results:34 patients (23 male and 11 female) resistant/refractory to lenalidomide were enrolled. The median age was 62 years (range, 39-77). The median time from diagnosis to enrollment was 62 months (range 8-179). 12 patients had high risk molecular markers including loss of 17p (6 pts), t(4;14) (1 pt) and del 13 by cytogenetics (5 pts). 70% had ≥3 prior regimens including 38% with ≥5 prior regimens; 56% had prior thalidomide, 59% had prior bortezomib, and 68% had prior SCT. Toxicity (at least possibly related to treatment) was mild and consisted primarily of myelosuppression: grade 3/4 neutropenia (21%); grade 3 thrombocytopenia (9%); and grade 3 anemia (12%). Grade 3/4 non-hematologic toxicities occurred in 24%: pneumonia (3%), non-infectious pneumonitis (3%), hyperglycemia (3%), edema(3%), fatigue(9%) skin rash(3%). Neuropathy occurred in 18% (12% grade 1; 6% grade 2). No thromboembolic events have occurred so far. Nine (26%) patients were confirmed responders (all PR), surpassing the threshold for a positive trial, and 18 (53%) had SD. With a median follow-up of 4 months (range:0-8), 65% remain progression free; 88% remain alive; and 12% have died, all due to progressive MM. Conclusions:Pom/dex is active and well tolerated in this heavily pre-treated population of lenalidomide-refractory MM patients. The majority of patients have not progressed and objective responses are seen in 26%. This study confirms that pomalidomide has non-cross resistance with lenalidomide and offers benefit for patients who have relapsed after other novel therapies. [Display omitted] Disclosures:Lacy:Celgene: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bergsagel:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria.

Phase I and Pharmacokinetic (PK) Study of Everolimus (RAD001) in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma (NHL).

Abstract 1712Poster Board I-738[Background and Purpose] Everolimus (RAD001), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR) serine-threonine kinase, which plays a key role in regulating cell growth and proliferation. Although anti-lymphoma effects of RAD001 have been shown in preclinical studies and one phase II clinical study in NHL, there is no PK data in NHL patients (pts). A phase I (P1) study was conducted to evaluate safety, PK profile, and efficacy of RAD001 in Japanese pts with relapsed and/or refractory NHL.[Patients and Methods] Pts with relapsed or refractory NHL, age ≥20, and PS 0-2 (ECOG) were enrolled and treated with RAD001, administered orally once daily at either 5 or 10 mg. Dose escalation was based on the clinical assessment of safety, incidence of dose-limiting toxicity (DLT), and probability of incidence of DLT. The latter probability distribution was estimated by a Bayesian logistic model, using prior information from other P1 trials with this agent in solid tumors. DLTs were evaluated in 6 pts at each dose level during the initial 28 days of study treatment (cycle 1). PK parameters were evaluated on days 1 and 15 of cycle 1. Response was assessed according to the International Workshop Criteria for NHL (1999).[Results] A total of 13 pts were enrolled into 2 cohorts as follows; 5 mg (7 pts, DLBCL: 2; MCL: 1; FL: 1; PTCL: 1; CTCL: 1; ALCL: 1) and 10 mg (6 pts, FL: 4; MCL: 1; ALCL: 1). 12 pts were evaluable for DLTs. 1 pt in the 5 mg cohort was inevaluable for DLTs due to early disease progression. No DLTs were observed at either dose level. Frequently encountered potentially drug-related adverse events (AEs) (≥40%) include leukopenia (8/13, 62%), thrombocytopenia (8/13, 62%), elevated AST (9/13, 69%), stomatitis (7/13, 54%), anemia (6/13, 46%), nasopharyngitis (6/13, 46%), and elevated ALT (6/13, 46%). Potentially drug-related Gr 3 or 4 toxicities include anemia (Gr 4 : 1), thrombocytopenia (Gr 4 : 1; Gr 3: 1), lymphopenia (Gr 4 : 1; Gr 3: 3), elevated LDH (Gr 3: 1), anorexia (Gr 3: 1), hyperglycemia (Gr 3: 1), fatigue (Gr 3: 1), hepatic function abnormal (Gr 3: 1), P. jiroveci pneumonia (Gr 3: 1), hyperkalemia (Gr 3: 1), and hypokalemia (Gr 3: 1). All toxicities cited above were transient and reversible. Non-infectious pneumonitis (Gr 1) was observed in 1 pt but resolved following discontinuation of RAD001 without additional therapy. Tmax was achieved within 4 hours, and Cmax and AUCtau both showed dose-proportional increases. The accumulation ratio after daily administration was approximately 2-fold. These data are consistent with those from a previous P1 study in solid tumors. A total of 4 objective responses (OR) were observed (summarized below):[Conclusions] RAD001 is well tolerated in this pt population at doses up to 10 mg/day and shows preliminary evidence of activity in relapsed or refractory NHL. The PK profile in pts with NHL is similar to that in pts with solid tumors. A global randomized phase III study to determine efficacy of RAD001 as adjuvant therapy following front-line R-CHOP induction in poor-risk DLBCL is currently ongoing. The data from this P1 study led directly to Japan's decision to participate in the global phase III study. DisclosuresShimada:Novartis Pharma K.K. Japan: Employment. Kobayashi:Novartis Pharma K.K. Japan: Employment.Dose (mg)ORHistologyDuration of response (mo)Status*5CRDLBCL12+Ongoing5PRDLBCL10+Ongoing10CRFL10+Ongoing10PRFL1.5d/c**As of 31 July 2009, 5/13 pts are still on active treatment.*as of 31 July 2009**treatment stopped due to Non-infectious pneumonitis

Everolimus (RAD001) in the treatment of advanced renal cell carcinoma: biology and pathways

Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), an intracellular serine/threonine kinase that regulates protein synthesis and cell growth, proliferation and survival. Dysfunction of mTOR has been implicated in a number of human illnesses including cancer and everolimus is used for a variety of therapeutic indications and is under evaluation in clinical trials for the treatment of cancer. Two phase I studies evaluating the dosing, toxicity, pharmacokinetics, pharmacodynamics and potential biomarkers of everolimus in advanced cancer have been reported. Daily doses of 10 mg and weekly doses of 50 mg of everolimus appear to inhibit relevant therapeutic targets in both tumour tissue and in skin but maximum-tolerated doses of everolimus were not determined formally in these studies. A phase III study of everolimus at 10 mg daily in the treatment of patients with advanced renal cell carcinoma who had failed prior treatment with sorafenib or sunitinib has also been reported. In this study everolimus was generally well tolerated, causing rash, stomatitis and fatigue in approximately a third of patients which generally were not severe. Hyperglycaemia, hypertriglyceridaemia and hypercholesterolaemia were reported in approximately two-thirds of patients but again were easy to manage and mainly of mild or moderate severity. Severe infections and non-infectious pneumonitis were reported in less than 5% of study participants but generally responded to standard therapies. Further work is necessary to define mechanisms of activity and toxicity of everolimus in the treatment of advanced renal cell carcinoma.

Noninfectious pneumonitis after blood and marrow transplant

Blood and marrow transplant recipients are predisposed to infectious and noninfectious pulmonary complications. Such complications can develop in 30-60% of blood and marrow transplant recipients and are the immediate cause of death in approximately 61%. This review will summarize recent developments in noninfectious complications that manifest as pulmonary infiltrates. Recent data in blood and marrow transplant recipients suggest that noninfectious pulmonary diseases may be more common than infectious complications. The main noninfectious pulmonary complications that present as pulmonary infiltrates include idiopathic pneumonia syndrome, peri-engraftment respiratory distress syndrome and diffuse alveolar hemorrhage. Bronchoalveolar lavage fluid shows progressively bloodier return and/or over 20% hemosiderin-laden macrophages in diffuse alveolar hemorrhage. Peri-engraftment respiratory distress syndrome differs from idiopathic pneumonia syndrome by its occurrence during the neutrophil peri-engraftment period and favorable response to corticosteroid therapy. The treatment of noninfectious pulmonary complications is not based on randomized clinical trials. Noninfectious pulmonary complications develop frequently in blood and marrow transplant recipients. The clinical presentations of idiopathic pneumonia syndrome, Peri-engraftment respiratory distress syndrome and diffuse alveolar hemorrhage may mimic pneumonia of infectious etiology. The therapeutic and prognostic implications mean that accurate diagnosis of these conditions is important.

Intravenous Busulfan Dosed Once Daily or Four Times Daily as Part of the Standard BuCy Preparative Regimen for Allogeneic Stem Cell Transplantation.

Intravenous busulfan (IVBu) (Busulfex ESP Pharma) is regularly substituted for oral busulfan as part of the standard busulfan and cyclophosphamide (BuCy) preparative regimen for allogeneic stem cell transplantation (ASCT). Oral busulfan was originally dosed 4 times daily, which led to the current accepted dosing schedule for IVBu. Pharmacokinetics (PK) and busulfan clearance allow for once daily dosing now that IVBu is available. We performed a retrospective review of 36 consecutive patients who received the BuCy preparative regimen with IVBu prior to ASCT. Twenty-one males and 15 females with a median age of 46 years (23–64) were treated for AML (n=15), ALL (n=1), CML (n=8), MDS (n=8), NHL (n=2), and multiple myeloma (n=2). IVBu was dosed 0.8 mg/kg 4 times daily for 16 doses (n=16) or 3.2 mg/kg once daily for 4 doses (n=20) on days -7 to -4, and cyclophosphamide was dosed 60 mg/kg once daily for two doses on days -3 and -2. IVBu was dosed by ideal or adjusted ideal body weight and no PK studies were done. Bone marrow (n=6) or peripheral blood (n=30) stem cells were infused on day 0 from HLA matched siblings (n=26) or unrelated donors (n=9), and one partially matched unrelated donor. Engraftment occurred in 34 patients (pts) (94%). Two pts who failed to engraft had bone marrow grafts with low numbers of total mononuclear cells infused. Regimen related toxicity (RRT) included mild VOD in 2 pts (5%) that self resolved, with one pt receiving IVBu 4 times daily and the other once daily. There was no seizure activity or non-infectious interstitial pneumonitis attributed to RRT in any patient. Other RRT were not significantly different between the patients who received 4 times daily or once daily IVBu. For all patients day 100 mortality was 17%, and at a median follow up of 12 months (1–54) 17 pts (47%) survive. Five of 16 pts (31%) survive who received 4 times daily IVBu, and 12 of 20 pts (60%) survive who received once daily IVBu. Three patients received once daily IVBu as outpatients and no patients received 4 times daily IVBu as outpatients. Financial review between day -7 to day 0, days 1–30, days 61–90, and day-7 to day 90 revealed patient charges were not significantly different at these time points between the once daily and 4 times daily dosing groups. In conclusion, this small retrospective single institution study revealed IVBu dosed once daily by ideal or adjusted ideal body weight appeared to have similar RRT, engraftment, survival and cost compared to 4 times daily IVBu when used as part of the BuCy preparative regimen for ASCT.

Sirolimus in pediatric patients: Results in the first 6 months post‐renal transplant

We report our experience with sirolimus in children during the first 6 months after renal transplantation. From July 2000 to January 2004, 66 children received 33 deceased donor and 33 living donor transplants. Maintenance immunosuppression included sirolimus 3 mg/m(2) in addition to prednisone and tacrolimus or cyclosporine. Patient survival was 100% and graft survival was 65 of 66. Seven children experienced acute rejection episodes. All were reversible with increased doses of corticosteroid. One case of graft failure was caused by ischemic renal injury. Adverse events included Epstein-Barr viremia (8 patients) with three cases of post-transplant lymphoproliferative disease (PTLD), cytomegalovirus viremia (4 patients), poor wound healing (4 patients), pneumonitis (3 patients), nephrotic syndrome (3 patients), perinephric abscess (1 patient) and insulin-dependant diabetes (2 patients). Sirolimus was discontinued in 13 children for adverse events predominantly for wound dehiscence and pneumonitis. Cholesterol levels >200 mg/dL were observed in 33 children. Thrombocytopenia (platelet count <140 000) was not observed. We concluded that early outcomes with sirolimus were acceptable with 98% graft survival and 11% incidence of acute rejection. Medication was discontinued in 20% for adverse events which included poor wound healing and non-infectious pneumonitis. Infections with cytomegalovirus and Epstein-Barr virus, and PTLD were also significant early complications. Therefore, a sirolimus-based regimen that is combined with both an interleukin-2 receptor antibody and a calcineurin inhibitor may be excessive immunosuppression for pediatric renal transplant recipients.

Beta3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice.

Hyperlipidemia promotes the chronic inflammatory disease atherosclerosis through poorly understood mechanisms. Atherogenic lipoproteins activate platelets, but it is unknown whether platelets contribute to early inflammatory atherosclerotic lesions. To address the role of platelet aggregation in diet-induced vascular disease, we studied beta3 integrin-deficient mice (lacking platelet integrin alphaIIbbeta3 and the widely expressed nonplatelet integrin alphavbeta3) in two models of atherosclerosis, apolipoprotein E (apoE)-null and low-density lipoprotein receptor (LDLR)-null mice. Unexpectedly, a high-fat, Western-type (but not a low-fat) diet caused death in two-thirds of the beta3-/-apoE-/- and half of the beta3-/-LDLR-/- mice due to noninfectious pneumonitis. In animals from both models surviving high-fat feeding, pneumonitis was absent, but aortic atherosclerosis was 2- to 6-fold greater in beta3-/- compared with beta+/+ littermates. Expression of CD36, CD40L, and CD40 was increased in lungs of beta3-/-LDLR-/- mice. Each was also increased in smooth muscle cells cultured from beta3-deficient mice and suppressed by retroviral reconstitution of beta3. These data show that the platelet defect caused by alphaIIbbeta3 deficiency does not impair atherosclerotic lesion initiation. They also suggest that alphavbeta3 has a suppressive effect on inflammation, the loss of which induces atherogenic mediators that are amplified by diet-induced hyperlipidemia.

Adult T-Cell Leukemia/Lymphoma Presenting as an Acute Noninfectious Pneumonitis

A 29-year-old man presented with a four-week history of pneumonic symptoms and progressive roentenographic infiltrates which were unresponsive to orally administered antibiotics. Bronchoscopy failed to identify an infectious etiology, but abundant atypical lymphocytes in the bronchial washings were present. A diagnosis of adult T-cell leukemia/lymphoma was subsequently made. After administration of cancer chemotherapy, the pneumonic symptoms and chest roentgenogram infiltrates resolved. This report suggests that ATL can present as an acute noninfectious pneumonitis.

Obstructive pneumonitis: a pathologic and pathogenetic reappraisal.

It is widely accepted that pneumonitis distal to an obstructing airway tumor is the result of infection. The authors performed a prospective study to reevaluate this concept and to clarify the nature of the pathologic findings underlying the observed radiographic changes. Specimens were examined for 50 consecutive patients undergoing resection of pulmonary carcinoma. Histologic changes interpreted as noninfectious were found in 42 cases. Findings suggestive of recent or remote infection were also present in nine of these 42 specimens and were localized predominantly in relation to small- to medium-sized airways (acute bronchitis or bronchiolitis); these changes were always present in a background of noninfectious pneumonitis. The authors conclude that the radiographic changes seen in airway obstruction in surgically excised lungs are usually due to consolidation of lung parenchyma by a noninfectious process. When infection does occur, it involves primarily the airways and is not likely to be radiographically detectable.