Background Immunological life-threatening complications frequently occur in post-hematopoietic stem cell transplantation (HSCT), despite matching recipient and donor (R/D) pairs for classical human leukocyte antigens (HLA). Studies have shown that R/D non-HLA disparities within the major histocompatibility complex (MHC) are associated with adverse effects post-HSCT. Methods We investigated the impact of mismatches of single-nucleotide polymorphisms (SNPs) in C4A / C4B genes, for showing the highest diversity in the MHC gamma block, on 238 patients who underwent HLA 10/10 unrelated donor (URD) HSCT. The endpoints were acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD) and mortality. One hundred and twenty-nine R/D pairs had 23 C4-SNPs typed by PCR-SSP (Gamma-Type™v.1.0), and 109 R/D pairs had these 23 SNPs identified by next-generation sequencing (NGS) using the Illumina platform. Results The percentage of patients who received HSC from HLA 10/10 donors with 1–7 mismatches was 42.9%. The R/D pairs were considered C4 mismatched when bearing at least one disparity. These mismatches were not found to be risk factors for aGVHD, cGVHD or mortality after unrelated HSCT when SNPs were analyzed together (matched or mm ≥ 1), independently or according to the percentage of incompatibilities (full match for 23 SNPs; 1–3 mm and >3 mm). An exception was the association between 1–3 mismatches at the composite of SNPs C13193/T14952/T19588 with the development of aGVHD (P = 0.012) and with grades III-IV of this disease (P = 0.004). Conclusion Our data are not consistent with the hypothesis that disparities in C4A / C4B SNPs increase the risks of post-HSCT adverse effects for the endpoints investigated in this study.
In this study, we report on major MRD or URD BMT outcomes in pediatric patients with SAA in Brazil. This was a retrospective study, which included 106 patients ≤18 years old who received a first BMT for SAA. All patients received bone marrow as graft source from an MRD (n = 69) or a URD (n = 37). Conditioning regimen was non‐myeloablative in 73.6% of cases, and GVHD prophylaxis comprised a calcineurin inhibitor plus methotrexate in 89.6% of patients. After a median follow‐up of 4.5 years after BMT, 81 patients are alive, with a 4‐year OS of 77% and no statistically significant difference between the MRD and URD groups (82% vs. 69%, respectively; P = .08). Grade III‐IV aGVHD at 6 months and cGVHD at 2 years were observed in 8% and 14% of cases, respectively, and were not statistically different between the groups. Twenty‐five (23%) patients died at a median of 2.9 months after BMT. Our study showed that 4‐year OS after BMT was not statistically different between MRD and URD recipients. This study shows that the outcomes of pediatric patients transplanted for SAA with a URD in Brazil are approaching those of MRD transplants. In contrast, OS after MRD BMT was lower than we would expect based on previous reports. The wide range of preparatory regimens used by the study centers highlights the need for standardized protocols for these children. Our findings provide a benchmark for future studies focused on improving BMT outcomes in this setting in Brazil.
Uncertainty still exists with the effects of allogeneic PBSCT on the clinical outcomes of patients with hematological malignancies. Our aim was analyzed retrospectively the clinical outcomes of 483 patients who underwent an allo PBSCT in 9 Brazilians centers from May 1994 to February 2004. The analyzes included patients with hematological malignancies who underwent PBSCT from HLA identical siblings donors treated with G-CSF at a dose of 10mgr/kg/day, 5 days. Median age was 34ys old (2–57), advanced disease was present in 58%, conditioning without irradiation was 85%; GVHD prophylaxis with MTX/CsA was 91%; CD34+ median was 4.7X106/kg (0.51–71.6); the median follow-up for surviving patients was 797 days (8–3420); median day for neutrophils and platelets engraftment was 15 and 14, respectively; cumulative incidence (CI) for ³ 2 aGVHD was 38%; extensive cGVHD 63%; CI for transplant relate mortality (TRM) 59%; CI for relapse 37%; the estimates of OS and DFS at 9 ys are 33% and 42, respectively. The following factors were significantly associated with better outcomes for engraftment, aGVHD, cGVHD, OS, DFS, relapse, and TRM in univariate analyzes, respectively: neutrophils and platelets engraftment: CD34+ cell dose > 2.8X106/kg, GVHD prophylaxis other than MTX/CsA, and sex match other than female donor for male recipient; aGVHD: age<43ys old, and CD34 dose > 4.7X106/kg; cGVHD: age < 25ys, sex match other than female donor for male recipient, advanced disease and CD3+ dose < 170X106/kg; OS: early disease; DFS: early disease, CD34+ dose > 4.7X106/kg; relapse: age> 25ys, CD34+ cell dose > 2.8X106/kg, and early disease; TRM: early disease. All the results remained significant in multivariate analyzes, but CD34+ dose and platelet engraftment; age and CD34+ dose in aGVHD; age and CD3+ in cGVHD, and age in relapse. In our experience, sex match, CD34+ dose, GVHD prophylaxis may influence the engrafment, and sex match and disease phase the cGVHD. Furthermore, advanced disease had a negative impact on OS and TRM;. CD34+ higher dose and early disease were associated with better DFS and lower relapse.
Purpose: Imatinib Mesilate is currently considered the most advanced therapy for CML due to its innovative molecular targeting mechanism of action, resulting in a high level of efficacy with a favorable toxicity profile which results in health-related quality of life (HRQL) benefits. We therefore decided to evaluate 230 patients with chronic myeloid leukemia (CML) treated with Imatinib Mesilate (Gleevec) as second line therapy, along 12 months, after failing Interferon (IFN) based therapy, due to lack of efficacy or toxicity, in an a Quality of Life (QoL) Study in Brazil, here presented as an interim analysis. Patients and Methods: From July 2002 until December 2003, 230 Patients from 21 Brazilian Medical Institutions, were enrolled in a Quality of Life (QoL) Study, where patients completed FACT-BRM questionnaire at baseline and during treatment. FACT-BRM includes 4 subscales appropriate for any chronic illness or treatment [physical (PWB), social/family (SFWB), emotional (EWB), functional (FWB)] and 2 treatment-specific subscales [BRM-physical (BRMP). The primary endpoint was the composite Trial Outcomes Index (TOI=PWB + FWB +BRMP + BRMCE). The questionnaire was applied at baseline (visit 0),monthly thereafter during the first 6 months on imatinib therapy (visits 1 through 7) and finally after 12 months on treatment (visit 8). Study population was distributed as following: gender 55,9% male and 44,1% female, mean age 46 years (range 18 to 76), Karnofsky status 100% in 56.7% and 80–90% in 29.9%. Initial Imatinib Mesilate dose was 400mg for 81,3% and 600mg for 18,7%. All patients were evaluated at baseline and at visits 7 (six months) and 8 (12 months) 147 (63.9%) and 45 (19.5%) patients were evaluated, respectively. Results: An increase of 5 or more from baseline was defined as a clinically relevant improvement 6. Patients had clinically relevant mean estimated improvement in TOI along treatment. After 1 treatment month TOI had an estimated mean increase of 5.4 (p<0.0001), after 6 months 7.4 (p<0.0001) and after 12 treatment months 9.8 (p<0.0051). TOTAL score improved significantly along treatment, with a clinically relevant mean estimated improvement of 6.5 (p<0.0001) already present after 1 treatment month. Improvement was equal to 8.0 (p=0.0007) and 10.7 (p=0.0369) after 6 and 12 treatment months. There were, also, significant increases in patients’ mean estimated FACTG (p<0.0001), BRMPHY (p<0.0001) and PWB (p<0.0001) along treatment. Conclusion: Imatinib offers remarkable QoL improvement even as a second line treatment in CML as reported previously on IRIS Study, where patients were allowed to cross over to the Imatinib treatment arm, after receiving Interferon based therapy.
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