Purpose To provide an updated joint ASCO/Infectious Diseases Society of American (IDSA) guideline on outpatient management of fever and neutropenia in patients with cancer. Methods ASCO and IDSA ...convened an Update Expert Panel and conducted a systematic review of relevant studies. The guideline recommendations were based on the review of evidence by the Expert Panel. Results Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. Recommendation Clinical judgment is recommended when determining which patients are candidates for outpatient management, using clinical criteria or a validated tool such as the Multinational Association of Support Care in Cancer risk index. In addition, psychosocial and logistic considerations are outlined within the guideline. The panel continued to endorse consensus recommendations from the previous version of this guideline that patients with febrile neutropenia receive initial doses of empirical antibacterial therapy within 1 hour of triage and be monitored for ≥ 4 hours before discharge. An oral fluoroquinolone plus amoxicillin/clavulanate (or clindamycin, if penicillin allergic) is recommended as empirical outpatient therapy, unless fluoroquinolone prophylaxis was used before fever developed. Patients who do not defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen should be re-evaluated and considered as candidates for inpatient treatment. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .
Community health factors play a role in determining outcomes for patients undergoing allogeneic hematopoietic cell transplantation. The transplant community, health advocacy groups, insurers, and ...government agencies must identify and remedy the reversible challenges and barriers to the successful application of this potentially lifesaving procedure for all patients who may benefit.
To provide an updated joint ASCO/Infectious Diseases Society of America (IDSA) guideline on antimicrobial prophylaxis for adult patients with immunosuppression associated with cancer and its ...treatment.
ASCO and IDSA convened an update Expert Panel and conducted a systematic review of relevant studies from May 2011 to November 2016. The guideline recommendations were based on the review of evidence by the Expert Panel.
Six new or updated meta-analyses and six new primary studies were added to the updated systematic review.
Antibacterial and antifungal prophylaxis is recommended for patients who are at high risk of infection, including patients who are expected to have profound, protracted neutropenia, which is defined as < 100 neutrophils/µL for > 7 days or other risk factors. Herpes simplex virus-seropositive patients undergoing allogeneic hematopoietic stem-cell transplantation or leukemia induction therapy should receive nucleoside analog-based antiviral prophylaxis, such as acyclovir.
prophylaxis is recommended for patients receiving chemotherapy regimens that are associated with a > 3.5% risk for pneumonia as a result of this organism (eg, those with ≥ 20 mg prednisone equivalents daily for ≥ 1 month or on the basis of purine analog usage). Treatment with a nucleoside reverse transcription inhibitor (eg, entecavir or tenofovir) is recommended for patients at high risk of hepatitis B virus reactivation. Recommendations for vaccination and avoidance of prolonged contact with environments that have high concentrations of airborne fungal spores are also provided within the updated guideline. Additional information is available at
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To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and on selection and treatment as outpatients of those with fever and neutropenia.
A literature search ...identified relevant studies published in English. Primary outcomes included: development of fever and/or infections in afebrile neutropenic outpatients and recovery without complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia, defervescence without regimen change, time to defervescence, infectious complications, and recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicrobials. An Expert Panel developed guidelines based on extracted data and informal consensus.
Forty-seven articles from 43 studies met selection criteria.
Antibacterial and antifungal prophylaxis are only recommended for patients expected to have < 100 neutrophils/μL for > 7 days, unless other factors increase risks for complications or mortality to similar levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully selected patients may be managed as outpatients after systematic assessment beginning with a validated risk index (eg, Multinational Association for Supportive Care in Cancer MASCC score or Talcott's rules). Patients with MASCC scores ≥ 21 or in Talcott group 4, and without other risk factors, can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of empirical antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin if penicillin allergic) is recommended as empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed.
In this multicenter, dose-ranging study of maribavir for the treatment of cytomegalovirus (CMV) infections deemed refractory or resistant to current antivirals, 67% of patients achieved clearance of ...CMV viremia within 6 weeks, with responses maintained for up to 24 weeks.
Abstract
Background
Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals (valganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains.
Methods
Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs).
Results
From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57–75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts <1000/µL were noted in 12/106 (11%) evaluable patients, with rates similar across doses.
Conclusions
Maribavir ≥400 mg twice daily was active against RR CMV infections in transplant recipients; no new safety signals were identified.
Clinical Trials Registration
NCT01611974.
Summary Background Cytomegalovirus reactivation occurs within 6 months in 60–70% of cytomegalovirus-seropositive patients after allogeneic haemopoietic stem-cell transplantation (HSCT), mainly due to ...immunosuppression associated with the procedure. Pre-emptive antiviral therapy reduces incidence of cytomegalovirus disease but can be toxic. To reduce the potential for disease and subsequent need for such antiviral drugs, we aimed to assess safety and efficacy of a cytomegalovirus therapeutic DNA vaccine compared with placebo. Methods In this exploratory double-blind, placebo-controlled, parallel group, phase 2 trial, up to 80 donor–recipient pairs and 80 unpaired recipients undergoing allogeneic HSCT were planned for enrolment at 16 transplant centres in the USA. Eligible recipients were cytomegalovirus-seropositive, 18–65 years old, without high-risk primary disease, T-cell depletion, previous vaccination for cytomegalovirus, or autoimmune diseases. We randomly allocated participants in both parallel groups in a 1:1 ratio to receive a cytomegalovirus therapeutic DNA vaccine (TransVax; Vical, San Diego, CA, USA) or placebo before conditioning and at 1, 3, and 6 months after transplantation. The vaccine contains plasmids encoding cytomegalovirus glycoprotein B and phosphoprotein 65 formulated with poloxamer CRL1005 and benzalkonium chloride. Randomisation was done by sequential allocation based on Pocock and Simon's method, and stratified by site, donor–recipient HLA matching status, and donor's cytomegalovirus serostatus. The primary outcome was the occurrence rate of clinically significant viraemia resulting in initiation of cytomegalovirus-specific antiviral therapy in the per-protocol assessable population. We assessed rates of adverse events in all participants who received at least one dose of vaccine or placebo. This study is registered with ClinicalTrials.gov , number NCT00285259. Findings We randomly allocated 108 participants (94 HSCT recipients and 14 paired donors) between June 29, 2006, and Dec 11, 2009. Enrolment of the paired arm was halted in February 2008 for logistical reasons. Safety was assessed in all participants; the efficacy population was restricted to 74 unpaired recipients. Groups were balanced for demographic and clinical variables. 19 (48%) of 40 vaccine recipients required cytomegalovirus-specific antiviral therapy, compared with 21 (62%) of 34 controls (p=0·145). However, during follow-up vaccine significantly reduced the occurrence and recurrence of cytomegalovirus viraemia and improved the time-to-event for viraemia episodes compared with placebo. The vaccine was well-tolerated; only one participant discontinued after an allergic reaction. Incidence of common adverse events after HSCT (eg, graft-versus-host disease or secondary infections) did not differ between groups. Interpretation We show proof of concept for an immunotherapeutic cytomegalovirus vaccine (TransVax) for clinically significant viraemia in the HSCT setting. The reported safety and efficacy outcomes support further development in a phase 3 trial, notwithstanding a lack of significant reduction in the use of cytomegalovirus-specific antiviral therapy compared with placebo in this phase 2 trial. Funding Vical and US National Institute of Allergy and Infectious Diseases.
We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity ...regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities.
Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years).
Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM.
Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.
Inhibition of the Janus-associated kinases (JAK) with ruxolitinib (RUX) reduces graft-versus-host disease (GVHD) in preclinical and clinical models. In total 19 allograft recipients with ...moderate/severe steroid-dependent chronic GVHD received RUX as ≥2nd line salvage. RUX was well tolerated, and led to complete/partial resolution of oral (92/7%), cutaneous (82/0%), hepatic (71/28%), gastro-intestinal (75/17%), musculoskeletal (33/67%), pulmonary (0/80%), scleroderma (0/75%), vaginal (0/75%), and ocular (0/100%) chronic GVHD. Overall 18 achieved partial response and 1 complete response according to NIH Consensus Criteria. Responses occurred early and were sustained which enabled discontinuation (68%) or reduction of steroids to physiologic doses (21%). We conclude that RUX is an effective steroid-sparing agent in chronic GVHD.
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