ABSTRACT
Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.
Subject(s)
Antilymphocyte Serum/administration & dosage , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/administration & dosage , Adolescent , Adult , Chronic Disease , Cyclosporine/administration & dosage , Disease-Free Survival , Female , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Humans , Immunosuppression Therapy/methods , Male , Methotrexate/administration & dosage , Middle Aged , Recurrence , Survival Rate , Time Factors , Transplantation Conditioning , Transplantation, HomologousABSTRACT
BACKGROUND: Citrulline is an amino acid produced by enterocytes. Serum citrulline concentration has been proposed as a marker of enterocyte mass and function. Our study focused on evaluation of citrulline levels in patients with diarrhea related to toxic intestinal damage (mucositis), intestinal graft versus host disease (GVHD), and other etiology of diarrhea (e.g., dysmicrobia) after allogeneic stem cells transplantation (SCT). MATERIAL AND METHODS: This was a prospective study in 11 adults (18 blood samples) with diarrhea developed after allogeneic SCT in 4/2011-1/2012 compared to twenty healthy control samples. RESULTS: The median (interquartile range) of citrulline levels was significantly lower in the transplanted patients group compared to healthy controls: 9.3 (3.62-15.38) vs. 33.3 (26.82-36.23) µmol/L, p<0.0001. The median values of citrulline in patients with post-transplant toxic intestinal mucositis (n=8, days 1-22 post-transplant) vs. intestinal GVHD (n=7, day 43-142) vs. other etiology of diarrhea (e.g., dysmicrobia) (n=3, day 120-127) were: 9.55 (2.95-12.03) vs. 5 (3.85-9.05) vs. 15.6 (15.45-18.3) mol/L resp. Serum citrulline levels were significantly higher in other (eg, dysmicrobic) etiology of diarrhea in comparison with mucositis (p=0.0336) and GVHD (p=0.0152). CONCLUSIONS: Citrulline levels are very low shortly after the myeloablative FLU/MEL or BuCY2 conditioning allogeneic SCT due to the toxic intestinal damage. Significantly low levels of citrulline were also in patients with intestinal GVHD later on. Other observations in larger groups of patients are necessary before any specific recommendation for citrulline levels monitoring in intestinal GVHD can be made.
Subject(s)
Citrulline/blood , Enterocytes/metabolism , Hematopoietic Stem Cell Transplantation/adverse effects , Adult , Biomarkers/blood , Case-Control Studies , Female , Humans , Male , Middle Aged , Pilot Projects , Transplantation, Homologous/adverse effectsABSTRACT
Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age ≥40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD.
Subject(s)
Antilymphocyte Serum/therapeutic use , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Myeloablative Agonists/therapeutic use , Transplantation Conditioning/methods , Acute Disease , Adolescent , Adult , Age Factors , Chronic Disease , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , HLA Antigens/immunology , Hematopoietic Stem Cell Transplantation/mortality , Histocompatibility Testing , Humans , Male , Middle Aged , Prospective Studies , Severity of Illness Index , Survival Rate , Transplantation, Homologous , Unrelated DonorsABSTRACT
BACKGROUND: Peripheral blood stem cells are an important source of hematopoietic stem cells (HSCs) for allogeneic transplantations. Some allogeneic donors mobilize HSCs poorly in response to the granulocyte--colony-stimulating factor (G-CSF). The estimation of the mobilization result in an individual donor is difficult due to the absence of suitable predictive factors. STUDY DESIGN AND METHODS: We analyzed the concentrations and kinetics of certain cytokines induced by G-CSF in 76 healthy donors and compared them with the mobilization efficiency. RESULTS: The levels of the most cytokines increased after the G-CSF application: sICAM, sVCAM, MMP-9, interleukin (IL)-6, TNF-α, sE-selectin, and fibronectin. The concentrations of SDF-1α and IL-8 decreased and VEGF and fractalkine remained unchanged. The premobilization concentrations of IL-6 (p = 0.0093) and TNF-a (p = 0.0006) correlated with preapheresis CD34+ cell count. The comparison of premobilization cytokine levels between better and worse mobilizers showed a difference for TNF-α (p = 0.0006) and IL-6 (p = 0.0682). The TNF-α level below cutoff of 3.6 pg/mL implied approximately 20 times higher risk of poor mobilization (odds ratio, 19.9; p = 0.0002). The immunophenotyping of CD34+ cells suggested a negative correlation between Day +5 CD34+ count and expression of CD11a (p = 0.0319) and a positive correlation with CD44 antigen expression (p = 0.0096). CONCLUSION: The concentrations of certain cytokines corresponded to the quality of HSC mobilization in healthy donors. Their levels measured before mobilization could probably serve as predictive factors for mobilization efficacy and prospectively detect donors who might profit from new mobilization molecules.
Subject(s)
Blood Donors , Cytokines/blood , Donor Selection , Granulocyte Colony-Stimulating Factor/pharmacology , Hematopoietic Stem Cell Mobilization , Adult , Blood Cell Count , Female , Filgrastim , Hematopoietic Stem Cells/drug effects , Humans , Immunophenotyping , Leukapheresis , Male , Middle Aged , Peripheral Blood Stem Cell Transplantation , Prospective Studies , Recombinant Proteins , Time Factors , Young AdultABSTRACT
BACKGROUND: Most results on the treatment of chronic myeloid leukaemia (CML) with imatinib were obtained from clinical trials that may differ from the routine practice. We report the results of treatment of consecutive patients with CML at ten major centres during 2000-2008. PATIENTS AND METHODS: Data reporting was retrospective in 2000-2004 and prospective from 2005 on. A total of 661 patients [301 women and 360 men; median age 51 (range, 15-83)] with Ph+CML were registered. The median follow-up was 46.1 months (0-122.2). RESULTS: Most patients were treated with first- (379; 57.3%) or second-line (193; 29.2%) imatinib; some of the patients underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (83; 12.6%), but 6.1% were treated with other modalities [40 patients; median age 66 (range, 32-83)]. The probability of overall survival (OS) at 5 years, according to Kaplan and Meier, was 88.9%, 77.5% and 68.7% for chronic-phase patients treated with first-line imatinib, second-line imatinib and first-line AHSCT, respectively, but only 25.2% for patients receiving other modalities. The OS was dependent on the disease phase and Sokal, Hasford and European group for blood and marrow transplantation (EBMT) risk scores (P<0.001; each). Only 46.2% of deaths in patients treated with other modalities were attributable to CML. Elderly patients over 65 years achieved similar response rates and progression-free survival to the younger ones. There was a trend for inferior results of AHSCT performed after the failure of imatinib (P=0.075), probably as a result of differences in EBMT risk scores (P<0.001). CONCLUSIONS: The ability to achieve results comparable to those of previous clinical studies in our CML cohort was influenced by centralised care. Decisions not to initiate imatinib or to delay AHSCT may have a negative impact on OS, but comorbidities may limit the treatment potential of imatinib in the elderly.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Benzamides , Czech Republic/epidemiology , Disease-Free Survival , Female , Hematopoietic Stem Cell Transplantation , Humans , Imatinib Mesylate , Kaplan-Meier Estimate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Middle Aged , Piperazines/therapeutic use , Prospective Studies , Pyrimidines/therapeutic use , Registries , Retrospective Studies , Slovakia/epidemiology , Transplantation, Homologous , Young AdultABSTRACT
BACKGROUND: Oral graft-versus-host disease (GVHD) is a significant complication after allogeneic stem cell transplantation (SCT) and there is no consistent information about its characteristics in patients after reduced-intensity conditioning regimen FLU/MEL (fludarabine 120 mg/m² and melphalan 140 mg/m²). MATERIAL/METHODS: This was a single-centre prospective observational study of patients after allogeneic SCT with FLU/MEL conditioning performed during the period 1/2005-12/2007. Characteristics of oral GVHD were observed in 71 patients. The observation was discontinued due to death, donor lymphocyte infusion (DLI) or new chemotherapy administration. RESULTS: In 10/2010, the median duration of the observation of the cohort of the patients was 13 (0.2-69) months, and 42 (35-69) months in the still-ongoing 20/71 (28%) patients. Oral acute GVHD had sporadic 7% incidence, whereas oral chronic GVHD was observed in 33% of patients and persisted with median duration of 188 (11-665) days. Clinical and histopathological features were similar in both acute and chronic oral GVHD and included mucosal lichenoid changes, erythema, ulcerations and pseudomembranes, satellite necrosis, apoptotic bodies and lichenoid interface inflammation. CONCLUSIONS: It is necessary to consider complex clinical symptomatology and pathological correlations when classifying the oral GVHD, because local oral symptoms and histopathological features in both acute and chronic oral GVHD forms can be similar. Even though the oral chronic GVHD was mild in the majority of patients, it can be considered as clinically significant due to its incidence, duration and symptomatology. The FLU/MEL conditioning regimen should not be considered as low-risk protocol in this context.
Subject(s)
Graft vs Host Disease/etiology , Melphalan/therapeutic use , Mouth Diseases/etiology , Stem Cell Transplantation/adverse effects , Transplantation Conditioning/adverse effects , Vidarabine/analogs & derivatives , Acute Disease , Adult , Aged , Chronic Disease , Female , Graft vs Host Disease/pathology , Humans , Male , Middle Aged , Mouth Diseases/pathology , Transplantation, Homologous , Vidarabine/therapeutic use , Young AdultABSTRACT
BACKGROUND: Gelclair is an oral lubricating gel used in the management of oral mucositis (OM). We evaluated its efficacy, tolerance and impact on oral cavity microbial colonization in patients with OM after allogeneic hematopoietic stem cells transplantation. MATERIAL/METHOD: Gelclair was administered in a group of 22 patients with active OM. A control group of 15 patients used other rinsing solutions (chlorhexidine, benzydamine, salvia). Tests with oral cavity swabs for microbiology analysis were performed once a week. RESULTS: The characteristics of OM in both groups were comparable, and rinsing solutions had satisfactory tolerability. There was no difference in the median improvement of oral intake and OM-related pain relief, which was assessed mostly as "slight effect". In the Gelclair group, the effect duration was longer (median 3 [0-5] vs. 1 [0-3] hours, p = 0.001). There was significant increase of Enterococcus faecalis and Candida sp. colonization of the oral cavity over the course of the hospitalization and significantly reduced incidence of such colonization in patients with OM in the Gelclair group: 1/22 (5%) vs. 6/15 (40%), p = 0.01. In vitro tests showed inhibited growth of Enterococcus faecalis and Candida sp. colonies within the area of the Gelclair application. CONCLUSIONS: Gelclair may be individually helpful in the management of OM and pain in patients after allogeneic stem cells transplantation. Its use did not lead to worsened oral bacterial and yeast colonization and probably even helped to protect mucosa from Enterococcus and Candida sp. Further studies based on larger cohorts are needed.
Subject(s)
Candida/drug effects , Enterococcus faecalis/drug effects , Hyaluronic Acid/pharmacology , Povidone/pharmacology , Stem Cell Transplantation/adverse effects , Stomatitis/drug therapy , Stomatitis/microbiology , Transplantation, Homologous/adverse effects , Benzydamine , Chlorhexidine , Drug Combinations , Facial Pain/drug therapy , Facial Pain/etiology , Humans , Hyaluronic Acid/therapeutic use , Povidone/therapeutic use , Prospective Studies , Stomatitis/etiology , Time FactorsABSTRACT
Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.
Subject(s)
Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 4/genetics , DNA-Binding Proteins/genetics , Hematopoietic Stem Cell Transplantation/methods , Histone-Lysine N-Methyltransferase/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Neoplasm, Residual/therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transcriptional Elongation Factors/genetics , Adult , DNA-Binding Proteins/metabolism , Female , Follow-Up Studies , Histone-Lysine N-Methyltransferase/metabolism , Humans , Male , Myeloid-Lymphoid Leukemia Protein/metabolism , Neoplasm, Residual/genetics , Neoplasm, Residual/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Remission Induction , Retrospective Studies , Survival Rate , Transcriptional Elongation Factors/metabolism , Translocation, Genetic , Transplantation Conditioning , Transplantation, HomologousABSTRACT
BACKGROUND: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic haematopoietic cell transplantation from unrelated donors. Anti-T-cell globulins (ATGs) might lower the incidence of GVHD. We did a prospective, randomised, multicentre, open-label, phase 3 trial to compare standard GVHD prophylaxis with ciclosporin and methotrexate with or without anti-Jurkat ATG-Fresenius (ATG-F). METHODS: Between May 26, 2003, and Feb 8, 2007, 202 patients with haematological malignancies were centrally randomly assigned using computer-generated centre-stratified block randomisation between treatment groups receiving ciclosporin and methotrexate with or without additional ATG-F. One patient in the ATG-F group did not undergo transplantation, thus 201 patients who underwent transplantation with peripheral blood (n=164; 82%) or bone marrow (n=37; 18%) grafts from unrelated donors after myeloablative conditioning were included in the full analysis set, and were analysed according to their randomly assigned treatment (ATG-F n=103, control n=98). The primary endpoint was severe acute GVHD (aGVHD) grade III-IV or death within 100 days of transplantation. The trial is registered with the numbers DRKS00000002 and NCT00655343. FINDINGS: The number of patients in the ATG-F group who had severe aGVHD grade III-IV or who died within 100 days of transplantation was 12 and 10 (21.4%, 95% CI 13.4-29.3), respectively, compared with 24 and nine (33.7%, 24.3-43.0) patients, respectively, in the control group (adjusted odds ratio 0.59, 95% CI 0.30-1.17; p=0.13). The cumulative incidence of aGVHD grade III-IV was 11.7% (95% CI 6.8-19.8) in the ATG-F group versus 24.5% (17.3-34.7) in the control group (adjusted hazard ratio [HR] 0.50, 95% CI 0.25-1.01; p=0.054), and cumulative incidence of aGVHD grade II-IV was 33.0% (n=34; 95% CI 25.1-43.5) in the ATG-F group versus 51.0% (n=50; 95% CI 42.0-61.9) in the control group (adjusted HR 0.56, 0.36-0.87; p=0.011). The 2-year cumulative incidence of extensive chronic GVHD was 12.2% (n=11; 95% CI 7.0-21.3) versus 42.6% (n=34; 95% CI 33.0-55.0; adjusted HR 0.22, 0.11-0.43; p<0.0001). There were no differences between treatment groups with regard to relapse, non-relapse mortality, overall survival, and mortality from infectious causes. INTERPRETATION: The addition of ATG-F to GVHD prophylaxis with ciclosporin and methotrexate resulted in decreased incidence of acute and chronic GVHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors. FUNDING: Fresenius Biotech GmbH.
Subject(s)
Antilymphocyte Serum/administration & dosage , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , T-Lymphocytes/immunology , Adolescent , Adult , Antilymphocyte Serum/adverse effects , Cyclosporine/administration & dosage , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , Methotrexate/administration & dosage , Middle Aged , Prospective Studies , Regression Analysis , Survival Analysis , Transplantation Conditioning , Transplantation, HomologousABSTRACT
The goal of this study was to analyze results and to determine factors affecting outcome of HLA-matched hematopoetic stem cells transplantation (MRD-HSCT) for patients with acute leukemia transplanted in first complete remission in Eastern European countries. Six hundred forty HSCT were performed between 1990 and 2006 for adults with acute myeloid (n = 459) and lymphoblastic (n = 181) leukemia. Two-year leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse incidence were 58 +/- 2%, 19 +/- 2%, and 23 +/- 2%, respectively. The cumulative incidence of NRM decreased from 22 +/- 2% for patients treated between 1990 and 2002 to 15 +/- 3% for transplantations performed between 2003 and 2006 (p = 0.02), despite increasing recipient age. In a multivariate analysis, time of HSCT affected both NRM and LFS. Among other prognostic factors, the use of TBI decreased relapse incidence and increased the LFS rate. We conclude that results of MRD-HSCT for acute leukemia in Eastern Europe improved over time as a consequence of decreased NRM. The use of TBI containing regimens appears advantagous.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Histocompatibility , Leukemia/diagnosis , Leukemia/therapy , Adolescent , Adult , Aged , Europe, Eastern , HLA Antigens , Hematopoietic Stem Cell Transplantation/mortality , Humans , Leukemia/mortality , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Prognosis , Recurrence , Remission Induction , Retrospective Studies , Survival Analysis , Time Factors , Transplantation, Homologous , Treatment Outcome , Whole-Body Irradiation , Young AdultABSTRACT
Peripheral blood stem cells are widely used as stem cell source for allografting. Progenitor cells can be effectively mobilized into peripheral blood in majority of healthy donors with a brief administration of G-CSF. A mobilization course in 111 donors (median age 40years) was retrospectively studied and the factors influencing the efficacy of mobilization were analyzed. The median number of CD34+ cells per kg recipient weight 5.1x10(6) was obtained after a median of two aphereses. The target cell dose (4.0x10(6)/kg) was reached in 69% of donors. Circulating CD34+ count and CD34+ yield were negatively associated with donor's age. Other independent factors associated with superior yield were precollection platelet and WBC counts. In multivariate analysis only CD34+ precount predicted for CD34+ yield. G-CSF had an acceptable short-term safety profile. Our data confirm that apheresis is a safe procedure in healthy including aged donors and suggest that older donors could be poorer mobilizers than younger.
Subject(s)
Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cells , Leukapheresis , Peripheral Blood Stem Cell Transplantation , Tissue Donors , Adolescent , Adult , Age Factors , Aged , Antigens, CD34 , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Leukocyte Count , Male , Middle AgedABSTRACT
We evaluated responses to the treatment and long-term outcomes of chronic myeloid leukemia patients treated with imatinib as first-line treatment in routine clinical setting from two countries with centralized tyrosine kinase inhibitors (TKIs) treatment. We assessed prognostic significance of European LeukemiaNet (ELN) 2006- and 2009-defined responses and the prognostic value of molecular responses at defined time points on 5-year survivals. Among the cumulative rates of incidence of hematologic, cytogenetic, and molecular responses and all important survival parameters, we evaluated the prognostic significance of different BCR-ABL transcript-level ratios (≤1%; >1%-≤10%; >10%) at 3, 6, 12, and 18 months (n = 199). The ELN optimal response criteria and their predictive role were significantly beneficial for event-free survival at all given time points. We found significant improvement in survivals of patients with BCR-ABL lower than 10% in the 6th and 12th months. Significantly better outcome was found in patients who achieved major molecular response (MMR) in the 12th month. The cumulative incidences of complete cytogenetic response (CCyR) and MMR were significantly associated with the molecular response in the 3rd month. The ELN response criteria and their predictive role were helpful at given time points; however, the 2009 definition did not significantly alter the prognostic accuracy compared with that of the 2006 definition. The significant value was observed for cytogenetic responses at the 6th and 12th month. Moreover, progression-free and event-free survivals were improved with MMR at the 12th month.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Fusion Proteins, bcr-abl/genetics , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Middle Aged , Prognosis , Survival Rate , Treatment Outcome , Young AdultABSTRACT
PURPOSE: Patients with Richter's syndrome (RS) have a poor prognosis with conventional chemotherapy. The aim of this study was to evaluate the outcome after autologous stem-cell transplantation (autoSCT) or allogeneic stem-cell transplantation (alloSCT) in RS. PATIENTS AND METHODS: A survey was sent to all European Group for Blood and Marrow Transplantation centers assessing transplantations performed for RS. Eligibility criteria included a diagnosis of RS or secondary lymphoma before SCT, age ≥ 18 years, and SCT performed from 1997 to 2007. Data were analyzed by descriptive statistics and methods from survival analysis. RESULTS: Fifty-nine patients were registered. Thirty-four patients had received autoSCT, mostly because of chemotherapy-sensitive disease, and 25 had received alloSCT, with 36% being refractory to chemotherapy at SCT. In 18 allograft recipients (72%), reduced-intensity conditioning (RIC) was used. Three-year estimates of the probabilities of overall survival and relapse-free survival (RFS) and the cumulative incidences of relapse and nonrelapse mortality were 36%, 27%, 47%, and 26% for alloSCT and 59%, 45%, 43%, and 12% for autoSCT, respectively. Taking into account the limitations set by the low number of events and age younger than 60 years, chemotherapy-sensitive disease and RIC were found to be associated with superior RFS after alloSCT in multivariate analysis. Factors with a significant impact on autoSCT could not be identified. CONCLUSION: Patients with RS who are sensitive to induction chemotherapy appear to benefit from consolidation with transplantation strategies, and prolonged survival was observed in a proportion of patients.
Subject(s)
Lymphoma/therapy , Adult , Aged , Combined Modality Therapy , Disease-Free Survival , Female , Hematopoietic Stem Cell Transplantation/methods , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Lymphoma/ethnology , Male , Middle Aged , Retrospective Studies , Survival Analysis , Syndrome , Transplantation Conditioning/methods , Transplantation, Autologous , Transplantation, HomologousABSTRACT
TP53 plays a pivotal role in the process of DNA repair and apoptosis. In 10-20% of patients with chronic lymphocytic leukemia (CLL), the TP53 pathway is affected. In this study, we analyzed the TP53 mutation status in 2435 consecutive CLL samples, including 1287 diagnostic samples and 1148 samples during follow-up, using FASAY (Functional Analysis of Separated Alleles in Yeast) and direct sequencing. In a cohort of 1287 diagnostic CLL samples, we identified 237 cases with TP53 variants, including mutations, temperature-sensitive variants, deletions, insertions and aberrant splicing variants (18.4%). In 1148 follow-up samples, no TP53 clonal evolution was observed.
Subject(s)
Biomarkers, Tumor/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation/genetics , Tumor Suppressor Protein p53/genetics , Alternative Splicing , Biomarkers, Tumor/metabolism , Blotting, Western , Chromosome Deletion , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Male , Mutagenesis, Site-Directed , Oligonucleotide Array Sequence Analysis , Prognosis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
This retrospective study evaluated the secondary clinical risk score at relapse, the prognostic significance of pre-transplant positron emission tomography (PET), and complete remission (CR) assessed by computed tomography (CT) after salvage chemotherapy before autologous stem cell transplant (ASCT) in 76 patients with relapsed/refractory Hodgkin lymphoma (HL). Median follow-up after ASCT was 23 months. Overall 11/20 PET-positive and 14/56 PET-negative patients relapsed after ASCT. In univariate analysis, only PET negativity before ASCT was significantly associated with better 2-year progression-free survival (PFS) (72.7 ± 6.3% vs. 36.1 ± 11.6%, p = 0.01) and 2-year overall survival (OS) (90.3 ± 4.1% vs. 61.4 ± 11.6%, p = 0.009). Other factors were not significant. In multivariate analysis, none of the evaluated factors were significant for PFS and OS. However, positive pre-transplant PET identified a population with worse PFS and OS at least in univariate analysis.
Subject(s)
Hodgkin Disease/diagnostic imaging , Positron-Emission Tomography , Adult , Female , Hematopoietic Stem Cell Transplantation , Hodgkin Disease/mortality , Hodgkin Disease/therapy , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , Recurrence , Remission Induction , Retrospective Studies , Salvage Therapy , Transplantation, Autologous , Treatment Outcome , Young AdultABSTRACT
We report a case of a successful mobilization and harvest of the peripheral blood stem cells (PBSCs) in imatinib-pretreated and nilotinib treated 52-year-old woman diagnosed with Philadelphia chromosome-positive and BCR-ABL (b2a2) positive chronic phase CML in 2/2002. She failed interferon-alfa and imatinib treatment. She achieved her first complete molecular remission after 16 months of nilotinib treatment and later on was mobilized with filgrastim at a dose of 10 ug/kg/day applied subcutaneously once daily. The total number of 2.98 x 10(6) CD34+ cells/kg was harvested on the fourth day of the mobilization. The autologous graft of the stem cells was cryopreserved and tested for the residual disease: the FISH revealed negative results and the RT-PCR was positive (BCR-ABL/ABL ratio 0,0017 in RQ-PCR). To our knowledge, this is the first report of successful PBSC harvest in a patient significantly pretreated with imatinib and nilotinib.
ABSTRACT
FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with internal tandem duplications (ITDs) accounting for up to 30% of its mutations. To analyze the impact of individual ITDs on the expression profile of immature myeloid cells, we have established 32D cell lines expressing nine different FLT3/ITDs isolated from AML patients and subjected them to whole genome expression profiling and 2DE/LC/MS proteomics. Our data indicate that in comparison to the controls, FLT3/ITD-positive 32D cells exhibit less mature expression profiles resembling early hematopoietic progenitors. Moreover, our results suggest that there exist biological differences among individual ITD variants.
Subject(s)
Blast Crisis/genetics , Blast Crisis/pathology , Genetic Variation , Leukemia, Myeloid, Acute/genetics , Tandem Repeat Sequences/genetics , fms-Like Tyrosine Kinase 3/genetics , Amino Acid Sequence , Animals , Blotting, Western , Cell Differentiation , Cell Division , Cell Line, Tumor , Cloning, Molecular , Exons , Gene Expression Profiling , Humans , Leukemia, Myeloid, Acute/pathology , Mice/genetics , Molecular Sequence Data , Mutation , Oligonucleotide Array Sequence Analysis , Retroviridae/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
BACKGROUND: Autologous stem cell transplantation (autoSCT) has an important role in the treatment of patients with symptomatic multiple myeloma (MM). Treatment options for myeloma have expanded in the past decade, and it seems that patients who are treated with novel drugs such as thalidomide and bortezomib for relapse after autoSCT have longer overall survival (OS). PATIENTS AND METHODS: Herein, we describe the long-term outcome of a cohort of 185 patients with newly diagnosed MM treated with autoSCT. We have analyzed factors that might predict for long-term survival. RESULTS: Following autoSCT, the overall response rate was 94% (173 of 185 patients); 29% (53 of 185 patients) were in complete remission (CR). Median time to progression (TTP) and OS from start of therapy were 39.8 months and 77.9 months, respectively. The median follow-up was 103.8 months (range, 60.8-144.8 months); 23% of the patients are alive and disease free, 21% of the patients are alive with relapse, and 56% of the patients have died. On multivariate analysis, factors associated with significantly better OS were International Staging System (ISS) disease stage < III (hazard ratio [HR], 2.6; P < .001), achievement of CR after autoSCT (HR, 2.8; P < .001) and use of thalidomide (HR, 4.3; P < .001) and/or bortezomib (HR, 7.3; P < .001) in posttransplantation relapse treatment. The patients' age, renal impairment, disease status before autoSCT and maintenance therapy with interferon-alpha (IFN-alpha) or IFN-alpha and dexamethasone did not significantly affect TTP and OS after transplantation. CONCLUSION: According to our results, the achievement of CR after transplantation, ISS stage other than III, and administration of thalidomide or bortezomib in posttransplantation relapse were significant parameters favoring long-term posttransplantation survival.
Subject(s)
Boronic Acids/therapeutic use , Hematopoietic Stem Cell Transplantation , Multiple Myeloma/therapy , Pyrazines/therapeutic use , Thalidomide/therapeutic use , Adult , Aged , Bortezomib , Disease Progression , Humans , Middle Aged , Multiple Myeloma/mortality , Recurrence , Transplantation, Autologous , Treatment OutcomeABSTRACT
Study on the normal saline vs povidone-iodine mouthwashes for oral mucositis (OM) prophylaxis in patients after high-dose chemotherapy comprising bischloroethyl nitrosourea etoposide ara-C melphalan (BEAM) or high-dose melphalan (HD-L-PAM) followed by autologous peripheral stem cell transplantation indicated that females have higher a incidence of OM compared to men, as reported by [Vokurka et al. 13:554-558, (2005)]. The multivariable analysis of larger cohort of 148 patients compliant with the original study protocol confirmed female gender to be an independent risk factor and predictor for OM. The HD-L-PAM (200 mg/m2) conditioning regimen revealed to be more toxic compared to BEAM as for incidence of OM grades 3-4 World Health Organization score. Body mass index, age, mouthwash solution used, and CD34+ cell number in the autologous graft were verified not to have an impact on OM incidence in this group of patients.