The association between HLA polymorphisms and PTLD was investigated in a case–control study, comparing 110 predominantly adult solid‐organ transplant recipients who developed PTLD to 5601 who did ...not. Donor and recipient HLA were analyzed. We detected a significant association between recipient HLA‐A26 and the development of PTLD (OR 2.74; p = 0.0007). In Caucasian recipients, both recipient and donor HLA‐A26 were independently associated with development of PTLD (recipient A26 OR 2.99; p = 0.0004, donor A26 OR 2.81; p = 0.002). Analysis of HLA‐A and ‐B haplotypes revealed that recipient HLA‐A26, B38 haplotype was strongly correlated with a higher incidence of EBV‐positive PTLD (OR 3.99; p = 0.001). The common ancestral haplotype HLA‐A1, B8, DR3, when carried by the donor, was protective against PTLD (OR 0.41; p = 0.05). Several other HLA specificities demonstrated associations with clinical and pathological characteristics as well as survival. These findings demonstrate the importance of HLA polymorphisms in modulating the risk for PTLD, and may be useful in risk stratification and development of monitoring and prophylaxis strategies.
The authors analyze a large cohort of solid organ transplant recipients and demonstrate novel associations between specific HLA polymorphisms and the risk to develop post‐transplant lymphoproliferative disease.
Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of ...bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30-50, 51-80 and >80 ml min(-1)). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl < or =50 ml min(-1) (severe-to-moderate) and >50 ml min(-1) (no/mild impairment). Response rates with bortezomib were similar (36-47%) and time to response rapid (0.7-1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl < or =50 vs >50 ml min(-1) (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl < or =50 vs >50 ml min(-1). These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-to-moderate vs no/mild impairment.
Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an ...antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse.
The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m(2), at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events.
Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/microL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less.
Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.
Bortezomib, an inhibitor of proteasomes (sites of protein degradation in cells), has activity against advanced multiple myeloma. This study compared bortezomib with high-dose dexamethasone relatively ...soon after a relapse of multiple myeloma had occurred with other treatments. Bortezomib was superior to dexamethasone in all end points and prolonged overall survival.
This study compared bortezomib with high-dose dexamethasone relatively soon after a relapse of multiple myeloma had occurred with other treatments. Bortezomib was superior to dexamethasone in all end points and prolonged overall survival.
During the past 10 years, advances in the treatment of multiple myeloma have improved survival moderately.
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In newly diagnosed disease, only high-dose chemotherapy followed by autologous hematopoietic stem-cell transplantation provides a survival benefit.
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The optimal therapy for relapsed myeloma is not established, but high-dose dexamethasone is commonly used.
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Response rates with this treatment are similar to those with vincristine, doxorubicin, and dexamethasone (VAD), and the dexamethasone component is estimated to account for 85 percent of the effect of VAD.
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The proteasome inhibitor bortezomib induces apoptosis, reverses drug resistance of multiple myeloma cells, and affects their microenvironment by . . .
Idiopathic Pneumonia Syndrome (IPS) is a common complication after allo-SCT and results in high mortality rates. Conventional treatment for IPS typically includes supportive care and high-dose ...corticosteroids (CS). Data suggests that TNF-α is important in the pathogenesis of IPS and that the TNF-α inhibitor etanercept may be useful for IPS treatment. We performed a retrospective comparison of consecutive patients treated at our center for IPS with CS only from 1999 to 2003 (group 1, n=22) or CS plus etanercept from 2004 to 2007 (group 2, n=17). In all, 18% of patients in group 1 vs 53% in group 2 were successfully taken off respiratory support and discharged from the hospital (P=0.039). OS was significantly better for recipients of CS plus etanercept (P=0.003). The estimated survival at 28 days and 2 years after IPS was 36.4% (95% CI 17-56%) and 9.1% (95% CI 2-25%) for group 1 and 88.2% (95% CI 61-97%) and 18% (95% CI 4-38%) for group 2, respectively. Our retrospective comparison suggests that the addition of etanercept to CS for IPS improves response rates and OS. However, outcomes remain limited in both groups, highlighting the need for more effective interventions to treat early and late complications of IPS.
This randomized trial compared lenalidomide plus dexamethasone with a placebo plus dexamethasone in patients in the United States and Canada who had multiple myeloma that was resistant to one or more ...other treatments. The addition of lenalidomide improved the time to progression and overall survival in these patients. Important adverse events were severe neutropenia and venous thromboembolism.
The addition of lenalidomide improved the time to progression and overall survival in patients with multiple myeloma.
Multiple myeloma causes nearly 11,000 deaths annually in the United States.
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Treatment with the immunomodulatory agent thalidomide or the proteasome inhibitor bortezomib has improved response rates, time to progression, and survival, but the side effects of fatigue, neuropathy, constipation, and thrombotic events remain a concern.
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In nearly all patients who receive these drugs or other chemotherapy, the disease eventually relapses and is subsequently resistant to treatment.
Lenalidomide is a thalidomide derivative that down-regulates interleukin-6 and nuclear factor κ-B and activates caspase 8 in vitro. The drug is up to 50,000 times as potent as its parent molecule in inhibiting . . .
Obesity, increasing worldwide, is common in patients undergoing hematopoietic cell transplantation (HCT). This complex physiological state may alter the outcome of cancer therapies by many mechanisms ...including direct effects on pathogenesis, host responses to disease and altered pharmacology of chemotherapy. Obesity has been associated with multiple adverse health outcomes. Reports of obese patients undergoing HCT are challenging to interpret because of the heterogeneity of obesity definitions, underlying diseases, graft sources and chemotherapy regimens employed. Compared with normal-weight patients, it appears that obese patients undergoing allogeneic HCT have a higher risk of non-relapse mortality and inferior survival whereas those receiving autologous HCT appear to have equivalent outcomes. These findings are also difficult to interpret because there is no consistent standard for calculating chemotherapy dose in this group and future studies on specific regimens in this population are urgently needed. Patients who have undergone bariatric surgery may be at risk for unexpected events because of impaired nutritional state and altered pharmacokinetics of oral drugs. We recommend that future studies utilize more consistent and biologically relevant definitions of obesity and that the pharmacokinetics and pharmacodynamics of specific conditioning regimens be studied. Until more evidence is available, a rationale is presented for dosing based on adjusted body weight. Moreover, recommendations are provided to guide future research efforts based on more definitive measurements of body fat and its distribution available through modern quantitative imaging techniques using dual energy X-ray absorptiometry or magnetic resonance imaging scanning.
Treatment options for steroid-refractory GVHD (SR-GVHD) are unsatisfactory and prognosis is poor. Inflammatory cytokines IL-2 and TNF-α are important mediators of GVHD and may be critical targets for ...therapy. We retrospectively reviewed our experience using combination anti-cytokine therapy of daclizumab and infliximab. Seventeen evaluable patients had a median age of 47 years (range 35-63). The conditioning regimen was myeloablative in 13 and non-myeloablative in 4 cases. GVHD occurred at a median of 49 days after transplant in 12 patients (range 21-231 days) and at a median of 46 days (range 25-119 days) after donor lymphocyte infusion in 5 patients. All patients had persistent or progressive GVHD despite 1-2 mg/kg/day of corticosteroids for a median of 7 days (range 2-26 days). They received a combination of daclizumab and infliximab for acute GVHD IBMTR severity index B (3), C (10) or D (4). Of the 17 patients analyzed, 47% responded to treatment, 24% had complete resolution of symptoms and 24% had partial responses. Survival was limited and all the patients died a median of 6.7 months (range 1.6-26) from transplant and 35 days from initiation of daclizumab/infliximab. This retrospective analysis suggests that combination anti-cytokine therapy with daclizumab/infliximab has significant activity in SR-GVHD, but outcomes remain poor. New methods to prevent and treat GVHD are urgently needed.
Most women with metastatic breast cancer have a response to various combinations of conventional-dose chemotherapy, but less than 5 percent of them are alive 10 years after the detection of ...metastatic spread.
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Several phase 2 trials performed in the late 1980s reported promising results for high-dose chemotherapy followed by autologous hematopoietic stem-cell transplantation in patients with chemotherapy-responsive metastatic breast cancer.
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These trials consistently reported high overall rates of response (combined complete and partial responses), ranging from 73 to 100 percent. Despite a median survival of only 10 to 24 months, 7 to 18 percent of patients in these studies . . .
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