Impact of cytotoxic and targeted antineoplastic drugs on the validity of the mitogen-induced interferon-gamma release assay for latent tuberculosis infection: results of a prospective trial at a comprehensive cancer center.

Abstract The T-SPOT.TB test (TS.TB), an interferon-gamma (IFN-γ) release assay (IGRA), is superior in diagnosing latent tuberculosis infection compared with the conventional tuberculin skin test (TST). However, whether cytotoxic chemotherapy and treatment with new-generation antineoplastic monoclonal antibodies affects the TS.TB is not certain. We evaluated the feasibility of using the TS.TB in this population. Sixteen cancer patients at high risk for tuberculosis exposure were prospectively evaluated with the TST and TS.TB. Blood samples were obtained 7.5 ± 89.3 days after the most recent cycle of antineoplastic therapy. Six patients (38%) were febrile within 24 h of blood sampling; high-dose corticosteroid therapy and profound treatment-induced neutropenia were present in 1 patient each. In all patients, TS.TB showed no evidence of latent tuberculosis infection. A robust mitogen-induced IFN-γ response was seen in samples from 14 patients (88%) despite therapy with high-dose corticosteroids, cyclophosphamide, fludarabine, gemtuzumab ozogamicin, and alemtuzumab. The presence of fever or profound neutropenia did not negatively impact mitogen response by peripheral lymphocytes. The 2 patients whose peripheral blood lymphocytes (> 500 cells/ml) failed to generate a cytokine response to ex vivo mitogen stimulation had refractory advanced cancer. Unlike the TST, a negative TS.TB provided interpretable results even in cancer patients undergoing new-generation immunosuppressive therapy.

Aerosolized amphotericin B lipid complex as adjunctive treatment for fungal lung infection in patients with cancer-related immunosuppression and recipients of hematopoietic stem cell transplantation.

STUDY OBJECTIVE: Aerosolized amphotericin B lipid complex (aeABLC) has been successfully used to prevent fungal disease. Experience with aeABLC as treatment of fungal lung disease is limited. DESIGN: We evaluated the safety and efficacy of aeABLC adjunct therapy for fungal lung disease in a retrospective study of 32 immunosuppressed adults. All values are given as ± standard deviation. SETTING: National Cancer Institute-designated Comprehensive Cancer Center. PATIENTS: Acute leukemia (69%) and severe neutropenia (63%) were common. Fifty-six percent of patients had undergone allogeneic hematopoietic stem cell transplantation 185 ± 424 days prior to aeABLC was commenced. MEASUREMENT AND MAIN RESULTS: High-dose corticosteroids were administered during aeABLC in 28% of patients. Fungal lung disease was proven or probable in 41% of patients. Most patients (78%) received concurrent systemic antifungal therapy for a median of 14 ± 18 days before aeABLC. The median cumulative aeABLC dose was 1050 ± 2368 mg, and the median duration of aeABLC therapy was 28 ± 130 days. Most patients (78%) received 50 mg aeABLC twice daily. Partial or complete resolution of fungal lung disease was noted in 50% of patients. In three patients (9%) modest cough, mild bronchospasm, and transient chest pain with accompanying nausea and vomiting resolved completely after discontinuation of aeABLC. No patient required hospitalization for drug toxicity or had a serious (grade III or IV) drug-related adverse event. CONCLUSION: Treatment with aeABLC was tolerated without serious toxicity and may be considered in the setting of severe immunosuppression, cancer, and/or hematopoietic stem cell transplantation in patients with difficult-to-treat fungal lung disease.

Characteristics of, and risk factors for, infections in patients with cancer treated with dasatinib and a brief review of other complications.

Dasatinib has transformed the treatment of chronic myelogenous leukemia, resulting in durable remissions and prolonged survival. The spectrum of infectious complications during and after dasatinib therapy is not known. Retrospective analysis of records among 69 patients treated with dasatinib showed that 35 (51%) developed 57 episodes of infection. Twenty-nine (51%) episodes occurred during neutropenia, and 25 (44%) were microbiologically confirmed. Compared with patients who did not develop infection with dasatinib therapy, patients with infection were significantly more likely to have acute lymphocytic leukemia (51% vs. 18%; p ≤ 0.005) and to have received high-dose corticosteroids (51% vs. 26%; p ≤ 0.05). Patients with infection were also more likely to have received dasatinib with another antineoplastic agent (57% vs. 35% without infection; p = 0.09). On multivariate analysis, treatment with three or more cycles of dasatinib increased the risk of infection (odds ratio 11.7; 95% confidence interval 2.5-54.3; p = 0.002). The presence of comorbidities tended to increase the risk of infection (odds ratio 3.9; 95% confidence interval 0.9-17.9; p = 0.07). Interestingly, viral infections, including a single case of cytomegalovirus colitis, were uncommon (7%). The rate of death in 57 patients during follow-up was non-significantly higher in patients with infection versus those without infection (35% vs. 18%; p = 0.18). Infection-associated deaths were noted in only two patients (10%) who had an infection and died. The results of our analysis suggest that antibacterial prophylaxis is important in patients who develop neutropenia during dasatinib therapy, although routine antifungal and anti-cytomegalovirus prophylaxis may not be necessary.

Multiple-dose granulocyte-macrophage-colony-stimulating factor plus 23-valent polysaccharide pneumococcal vaccine in patients with chronic lymphocytic leukemia: a prospective, randomized trial of safety and immunogenicity.

BACKGROUND: For the current study, the authors sought to determine whether administration of multiple-dose granulocyte-macrophage-colony-stimulating factor (GM-CSF) could improve response to standard 23-valent polysaccharide pneumococcal vaccine (PPV) in patients with chronic lymphocytic leukemia (CLL). METHODS: Patients were allocated randomly to receive PPV either alone or with 3 doses of GM-CSF (250 microg) given before or after vaccination. Serum was obtained before, 4 weeks after, and 12 weeks after vaccination for antibody determination. Thirty-two patients with CLL were given PPV. They were randomized to receive 3 doses of GM-CSF either before or after vaccination or to receive no GM-CSF. RESULTS: A 4-fold rise in immunoglobulin G (IgG) to capsular polysaccharides from Streptococcus pneumoniae types 4, 6B, 9V, 14, 19F, and 23F occurred in <10% of patients in each of the 3 groups. There were no differences in geometric mean IgG levels in any of the 3 groups 4 weeks or 12 weeks after vaccination. CONCLUSIONS: In patients with CLL, the response to pure polysaccharide pneumococcal vaccine was low despite immune enhancement with multiple doses of GM-CSF. In all patients, reactogenicity was minor.

Infections in 100 cord blood transplantations: spectrum of early and late posttransplant infections in adult and pediatric patients 1996-2005.

Cord blood-derived stem cells are successfully used in the treatment of cancer and congenital disorders in children. This alternative source of stem cells is also explored for adult cancer patients with limited donor options. However, delayed engraftment, prolonged neutropenia, secondary graft loss, and graft-versus-host disease (GVHD) in recipients of cord blood transplantation (CBT) make opportunistic infections a serious concern. We evaluated the spectrum of infections in adults and children undergoing CBT at our National Cancer Institute-designated comprehensive cancer center. The infection incidence rate ratio (total infection episodes/days at risk [survival after CBT] x 100) was 2.4 times higher in 35 adult patients than in 62 children, especially in adults with neutropenia (3 x higher) and GVHD (1.9 x higher). Ninety-two percent of fungal infection episodes occurred within 100 days after transplantation; half of these infections occurred in the first 30 days after CBT. Most bacterial infections (80%) were also diagnosed in the first 100 days, whereas late (>100 d) post-CBT cytomegalovirus and varicella zoster virus infections occurred only in children with chronic GVHD. Multivariate analysis showed that resolution of lymphocytopenia (> or =1000 cells/microL) (hazard ratio [HR] 0.71; p < 0.0001) and successful engraftment (HR 0.20; p < 0.0001) were associated with a low risk of serious infection. Children (HR 0.36; p < 0.0002) with sustained engraftment (HR 0.39; p < 0.004) and those with cancer in remission (HR 0.47; p < 0.007) were less likely to die from infection. More effective measures for surveillance and prevention of late cytomegalovirus and varicella zoster virus infections in children with CBT and chronic GVHD are needed.

Dose-related safety and immunogenicity of baculovirus-expressed trivalent influenza vaccine: a double-blind, controlled trial in adult patients with non-Hodgkin B cell lymphoma.

In 27 patients randomized to receive commercial trivalent influenza vaccine (TIV) containing 15 microg of the hemagglutinin (HA) of influenza A (H3N2 and H1N1) and B virus or a recombinant vaccine (rHAO) containing 15, 45, or 135 microg of each HA, reactogenicity was minor. Among patients with similar prevaccination titers, 40% given 45 microg and 60% given 135 microg of rHAO developed an increase in influenza A/H3 neutralizing antibody levels; there were no increases in 4 given TIV. For each vaccine, the highest frequencies of increases in neutralizing antibody levels and the highest mean titers occurred in those given the 135- microg vaccine.

Recombinant interferon gamma1b immune enhancement in 20 patients with hematologic malignancies and systemic opportunistic infections treated with donor granulocyte transfusions.

BACKGROUND: The response to antifungal therapy alone often is suboptimal in patients with cancer who have therapy-refractory neutropenia, and even donor-derived granulocyte transfusions (GTX) are not always successful. The authors evaluated the safety and efficacy of immune enhancement using recombinant interferon gamma1b (rIFN-gamma1b) in patients with cancer who received GTX for refractory, systemic, opportunistic infections. METHODS: Twenty recipients of high-dose donor GTX ( approximately 5.5 x 10(10) neutrophils per transfusion) who had received concurrent rIFN-gamma1b between October 2001 and December 2004 were evaluated retrospectively. RESULTS: The median age (+/- standard deviation [SD]) was 45 +/- 17 years. Ten patients (50%) were men, 17 patients (85%) had leukemia, and 3 patients (15%) had myelodysplastic syndrome. The median +/- SD Acute Physiology and Chronic Health Evaluation II score was 15 +/- 4 (range, 7-22). Most patients (n = 18 patients; 90%) had recurrent or refractory cancer. In 6 patients (30%) who received allogeneic hematopoietic stem cell transplantation, GTX plus rIFN-gamma1b was given a median +/- SD of 26 +/- 100 days (range, 12-372 days) after transplantation. Seventeen patients (85%) had neutropenia during GTX therapy. Five patients (25%) had possible invasive fungal infection, 3 patients (15%) had probable invasive fungal infection, and 11 patients (55%) had proven invasive fungal infection. One patient (5%) had refractory Pseudomonas aeruginosa sepsis. Eight patients (40%) received corticosteroids during GTX plus rIFN-gamma1b therapy. Patients received a median +/- SD of 8 +/- 7 GTX doses (range, 4-28 doses) and 9 +/- 7 rIFN-gamma1b doses (range, 1-28 doses), for a mean +/- SD cumulative dose (CD) of 400 +/- 2621 microg. Other concomitant cytokines were granulocyte-colony stimulating factor (12 +/- 3 doses; CD, 6720 +/- 4721 microg) in 15 patients (75%) and granulocyte-macrophage-colony stimulating factor (12 +/- 9 doses; CD, 4750 +/- 4410 microg) in 14 patients (70%). Four patients (20%) developed fever, and 2 patients (10%) developed skin rashes. Reversible liver dysfunction (n = 3 patients; 15%) and tachycardia (n = 1 patients; 5%) were considered rIFN-gamma1b-associated adverse reactions; whereas, in 1 patient (5%), transient dyspnea was attributed to GTX. Four weeks after therapy started, 9 patients (45%) had complete or partial resolution of infection; and, in another 3 patients (15%), the invasive fungal infection had become stable. CONCLUSIONS: The current results indicated that no serious adverse events were associated with rIFN-gamma1b immune enhancement in patients with systemic opportunistic infections who received donor GTX therapy.