Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo-HCT were 28% (95% confidence interval (CI), 25-31), 35% (95% CI, 32-38) and 40% (95% CI, 37-42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73-85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients.
The fludarabine (FLU)/melphalan (MEL) conditioning regimen containing FLU and high-dose MEL was analyzed in comparison with the BU/CY2 regimen to characterize oral mucositis (OM) and risk factors. OM incidence significantly varied between BU/CY2 and FLU/MEL (100 vs 78%, P ¼ 0.004), but the incidence of severe OM grades 3-4 WHO and kinetics of OM were fully comparable. Patients with OM persisting on day þ 21 had more acute GVHD (68 vs 32%, P ¼ 0.005), which tended to occur earlier than among those without such prolonged OM. Multivariate analysis showed significant dependency of acute GVHD on severity and prolonged duration of OM and significant correlation between OM severity and its prolonged duration. Body surface area-based dosing in the FLU/MEL regimen led to a wide range of MEL doses administered per kilogram body weight (2.5-5.2 mg/kg, median 3.5). In multivariate analysis, MEL dose per kilogram of body weight was found to be a significant predictor of OM incidence and severity. Female gender and lower body mass index were less important variables than the fact that the actual dose of MEL administered per kilogram of body weight was relatively high when the dosage was calculated on the basis of body surface area.
Monoclonal antibodies binding the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, are widely used targeted therapeutics for the treatment of patients with colorectal cancer. The clinical significance of these drugs has so far been associated with combined chemotherapy or radiation. It has been shown that these treatment strategies have their clinical limitations and do not fully exploit the immunomodulatory effect of these drugs. In this review, we discuss the mechanisms of immunomodulation together with the anticancer immune response to the monoclonal antibodies targeted to the EGFR. The combination of anti-EGFR monoclonal antibodies with other immunotherapeutic treatment modalities certainly brings new opportunities for targeted therapy in patients with colorectal cancer.
For young patients with high-risk CLL, BTK-/PI3K-inhibitors or allogeneic stem cell transplantation (alloHCT) are considered. Patients with a low risk of non-relapse mortality (NRM) but a high risk of failure of targeted therapy may benefit most from alloHCT. We performed Cox regression analyses to identify risk factors for 2-year NRM and 5-year event-free survival (using EFS as a surrogate for long-term disease control) in a large, updated EBMT registry cohort (n= 694). For the whole cohort, 2-year NRM was 28% and 5-year EFS 37%. Higher age, lower performance status, unrelated donor type and unfavorable sex-mismatch had a significant adverse impact on 2-year NRM. Two-year NRM was calculated for good- and poor-risk reference patients. Predicted 2-year-NRM was 11 and 12% for male and female good-risk patients compared with 42 and 33% for male and female poor-risk patients. For 5-year EFS, age, performance status, prior autologous HCT, remission status and sex-mismatch had a significant impact, whereas del(17p) did not. The model-based prediction of 5-year EFS was 55% and 64%, respectively, for male and female good-risk patients. Good-risk transplant candidates with high-risk CLL and limited prognosis either on or after failure of targeted therapy should still be considered for alloHCT.
Our data showed that the pre-transplant level of MRD in patients with normal karyotype AML harboring NPM1 mutation in CR provides important prognostic information, which as an independent prognostic factor predicts transplant results.
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