Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the current study, we have analyzed the efficacy of cyclosporine A (CSA) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis in the fludarabine plus melphalan or busulfan reduced intensity regimen (RIC) setting in a series of 44 patients receiving allogeneic transplantation from an unrelated donor. Only 23% were in the first complete remission at the time of transplant. Cumulative incidence of grades II-IV and III-IV acute GVHD (aGVHD) was 53% and 23%, respectively. Fifty-six percent had equal to or greater than grade 2 gut involvement. Cumulative incidence of overall and extensive chronic GVHD (cGVHD) was 93% and 63%, respectively. Ninety-two percent of patients who were evaluable +100 days after transplant were in complete remission. Relapse rate was 25% at 2 years. Event free (EFS) and overall survival (OS) at 2 years were 52%. Pharmacokinetic assays of mycophenolic acid (MPA) showed a therapeutic area under the curve (AUC) at the dosage of 3 g daily, although a large inter- and intraindividual variations of MPA plasma levels were found. In conclusion, the combination of CSA plus MMF in the fludarabine plus melphalan or busulfan RIC setting is feasible. Regarding GVHD, this combination allowed to control aGVHD but lead to a high incidence of cGVHD, so that newer strategies are required, especially in trying to decrease gastrointestinal involvement.
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PMID:Reduced-intensity conditioning allogeneic transplantation from unrelated donors: evaluation of mycophenolate mofetil plus cyclosporin A as graft-versus-host disease prophylaxis. 1848 92

One hundred ten patients with multiple myeloma (MM) failing to achieve at least near-complete remission (nCR) after a first autologous stem cell transplantation (ASCT) were scheduled to receive a second ASCT (85 patients) or a reduced-intensity-conditioning allograft (allo-RIC; 25 patients), depending on the human leukocyte antigen (HLA)-identical sibling donor availability. There was a higher increase in complete remission (CR) rate (40% vs 11%, P = .001) and a trend toward a longer progression-free survival (PFS; median, 31 months vs not reached, P = .08) in favor of allo-RIC. In contrast, it was associated with a trend toward a higher transplantation-related mortality (16% vs 5%, P = .07), a 66% chance of chronic graft-versus-host disease and no statistical difference in event-free survival and overall survival. Although the PFS plateau observed with allo-RIC is very encouraging, this procedure is associated with high morbidity and mortality, and therefore it should still be considered investigational and restricted to well-designed prospective clinical trials. This trial is registered at ClinicalTrials.gov ID number NCT00560053.
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PMID:A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. 1894 79

Certain leukemias have a high relapse risk even after allo-SCT, and GVHD prophylaxis with calcineurin inhibitors (CNIs) may interfere with a possible GVL effect. Therefore, we replaced CYA by sirolimus in patients with high relapse risk. In contrast to CNIs, sirolimus promotes the generation of regulatory T-cells and has potent antineoplastic activity. Sirolimus has been used in combination with CNI for GVHD prophylaxis in hematopoietic SCT. However, no CNI-free prophylactic regimen with sirolimus has been evaluated so far. Within the FLAMSA-RIC protocol, 15 patients received GVHD prophylaxis with sirolimus and mycophenolate mofetil (MMF). The underlying diagnoses were relapsed or refractory T-ALL (n=3), AML with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) or mixed-lineage leukemia-partial tandem duplication (MLL-PTD; n=10; 5 with refractory disease) and CML in refractory myeloid blast crisis (n=2). All evaluable patients (n=14) were engrafted. Grades II-IV acute GVHD occurred in 21% and chronic GVHD in 30% of patients. Non-relapse mortality rate was 14%. No thrombotic microangiopathy or sinusoidal obstruction syndrome was observed. Three patients with FLT3-ITD+ AML relapsed after a median of 112 days. At a median follow-up of 10 months after transplantation, 10 patients are alive and in complete remission. In conclusion, sirolimus-based GVHD prophylactic regimens deserve further investigation.
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PMID:Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study. 1901 60

Acute renal failure (ARF) is a life-threatening complication after allogeneic stem cell transplantation (Allo-HSCT). Identification of ARF risk factors could be useful to develop preventive strategies for patients at high risk. The goal of this study was to evaluate the incidence and risk factors of ARF after reduced intensity conditioning Allo-HSCT (Allo-RIC). We included 188 consecutive patients who underwent Allo-RIC in our center between January 1999 and December 2006. ARF was defined as a decrease of at least 25% in baseline estimated glomerular filtration rate (GFR) calculated by modification of diet in renal disease (MDRD) equation. Conditioning consisted of fludarabine (Flu) 150 mg/m(2) in combination with busulfan (Bu) 8-10 mg/kg (n = 61), melphalan (Mel) 140 mg/m(2) (n = 115), cyclophosphamide (Cy) 120 mg/kg (n = 7) or low-dose total-body irradiation (TBI) 2 Gy (n = 5). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) alone (n = 3) or in addition to methotrexate (MTX; n = 132) or mycophenolate mofetil (MMF; n = 51). The cumulative incidence of ARF at 1 year was 52% (n = 97 patients) after Allo-RIC. Most cases (86%) occurred within the first 3 months, and the main cause was the administration of CsA (71%). The risk factors associated with ARF in multivariate analysis were: administration of MTX (hazard ratio [HR] 1.9, P =.02), more than 3 lines of therapy prior to Allo-RIC (HR 1.8, P = .01), diabetes mellitus (HR 2.1, P < .01), and GVHD grade III-IV (HR 2.1, P = .015). In multivariate analysis, ARF was an independent risk factor for 1-year nonrelapse mortality (NRM) (HR 3, 95% confidence interval [CI]: 1.5-6, P = .002). Patients who experienced ARF had lower 1-year overall survival (OS; 53% versus 74%, P < .05). ARF is a frequent complication in patients after Allo-RIC, and it has a negative impact on outcome. Identification of ARF risk factors could help to avoid exposure to nephrotoxic drugs during the follow-up in patients at high risk.
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PMID:Study of kidney function impairment after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. A single-center experience. 1913 39

Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced-intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% confidence interval [CI] 10%-21%) and 33% (95% CI 25%-41%), respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and the Karnofsky Performance Scale (KPS) <90 were significant risk factors for TRM, PFS, and OS, whereas chemosensitivity at transplantation was not. Dose intensity of the conditioning regimen (RIC versus NST) did not impact outcomes. Unrelated donor HCT with RIC/NST can salvage some patients with relapsed/refractory HL, but relapse remains a common reason for treatment failure. Clinical studies should be aimed at reducing the incidence of acute graft-versus-host disease (GVHD) and relapse.
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PMID:Unrelated donor reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. 1913 49

Allogeneic hematopoietic SCT (allo-HCT) is the only curative therapy for myelodysplastic syndrome (MDS). Numerous myeloablative (MA), nonmyeloablative SCT (NST) and reduced conditioning transplant (RIC) studies have included MDS patients. Twenty-four MA HCT studies published from 2000 and 2008 reported OS and disease-free survival (DFS) ranging from 25 and 16% at 2 years to 52 and 50% at 4 years. In these publications, the incidence of grades II-IV acute GVHD was 18-100%, chronic GVHD 13-88%, relapse risk 24% at 1 year to 54.5% at 4 years and TRM 19% at day 100 to 61% at 5 years. From 2003 to 2008, 30 publications combining RIC and NST reported OS and DFS from 22 and 20% at 2 years to 79 and 79% at 4 years. Incidence of grades II-IV acute GVHD ranged from 9 to 63%, chronic GVHD 18 to 80%, relapse risk 6 to 61% and TRM 0% at day 100 to 34% at 5 years. The wide range in the published results leaves many unanswered questions. Although no ideal transplant conditioning has emerged, many of the MA and RIC studies used BU-based regimens and used a recipient age cutoff of 50-55 years for MA HCT. Similarly, there is no agreement on the use of induction or hypomethylating therapy before HCT, but azacitidine and decitabine are gaining increasing attention as a bridge to HCT. Until recently, the International Prognostic Scoring System (IPSS) dictated the use and timing of HCT. The WHO classification and WHO Prognostic Scoring System (WPSS) may be better suited in predicting the outcomes and should probably be incorporated in transplant algorithms. Most published MDS transplant series combine matched related donors (MRD) and matched unrelated donors (MUD). Umbilical cord blood (UCB) grafts will likely broaden the population of MDS patients eligible for allografting, but outcome data for MDS are scant. At this time, it is reasonable to consider the availability of an MRD or MUD as separate from an UCB graft in the decision of transplantation for MDS. The development of RIC, improvements in supportive therapy and alternative donor selection will provide better OS for MDS patients undergoing transplantation. Simultaneously, better understanding and medical therapy of MDS are leading us to re-examine patient selection and the timing of HCT. The results of HCT for MDS continue to improve together with the outlook of patients afflicted with myelodysplasia.
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PMID:The evolution of hematopoietic SCT in myelodysplastic syndrome. 1925 32

Neurological complications (NC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and life-threatening in most cases. They may involve either the central (CNS) or peripheral nervous system (PNS). The aim of this study was to describe incidence and characteristics of NC after reduced-intensity conditioning allo-HSCT (allo-RIC), an unexplored setting. For this purpose, we reviewed 191 consecutive patients who underwent this procedure at our institution between January 1999 and December 2006. The median follow-up for survivors was 48 months (3-98 months). RIC included fludarabine (Flu) 150 mg/m(2) in combination with busulfan (Bu) 8-10mg/kg (n=61), melphalan (Mel) 70-140 mg/m(2) (n=119), cyclophosphamide (Cy) 120 mg/kg (n=7), or low-dose total body irradiation (TBI) 2Gy (n=4). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) in combination with methotrexate (MTX; n=134) or mycophenolate mofetil (MMF; n=52). Twenty-seven patients (14%) developed a total of 31 NC (23 CNS and 8 PNS) for a 4-year cumulative incidence of 16% (95% confidence interval [CI] 11-23). CNS complications included nonfocal encephalopathies in 11 patients, meningoencephalitis in 5 patients, and stroke or hemorrhage in 4. PNS complications consisted of 5 cases of mononeuropathies and 3 cases of polyneuropathies. Drug-related toxicity was responsible for 10 of the 31 events (32%) (8 caused by CsA). Interestingly, 14 of the 23 CNS events (61%) and only 1 of the 8 PNS complications (13%) appeared before day +100 (P=.01). Overall, patients presenting NC showed a trend for higher 1-year nonrelapse mortality (NRM) (37% versus 20%, P=.08). In patients with CNS involvement, 1-year NRM was significantly worse (42% versus 20%, P=.02). CNS NC also had a negative impact on 4-year overall survival (OS; 33% versus 45%, P=.05). In conclusion, our study showed that NC are observed after allo-RIC and have diverse features. NC affecting the CNS have earlier onset and worse outcome than those involving the PNS.
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PMID:Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation. 1982 4

The influence of graft composition on the outcome of reduced-intensity (RIC) allogeneic PBSC transplantation (allo-PBSC) remains controversial. In this study, we analyzed the impact of CD34+ cell dose on the incidence of GVHD, and on the outcome after allo-PBSC, in 103 patients with hematological malignancies, using a uniform RIC regimen. The following variables were included in statistical analysis: (1) number of C34+ cells, (2) high-risk vs low-risk disease status, (3) matched related vs matched unrelated donor, (4) female donor to male recipient vs any other combination, (5) age of recipient (above vs below the median). Univariate and multivariate analysis did not reveal any association between CD34+ cell dose and acute grade-2 to grade-4, cGVHD, non-relapse mortality (NRM), relapse rate (RR) and OS. High-risk disease status was the only variable independently associated with increased NRM (P=0.001), increased RR (P=0.012) and decreased OS (P<0.001). The same results were obtained when analysis was restricted to a subgroup of 55 patients with myeloid neoplasms. The influence of graft composition on the outcome of RIC allo-PBSC should be further investigated via well-controlled randomized prospective studies.
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PMID:The number of infused CD34+ cells does not influence the incidence of GVHD or the outcome of allogeneic PBSC transplantation, using reduced-intensity conditioning and antithymocyte globulin. 1994 41

Mycophenolate mofetil (MMF) in combination with CsA seems to lead to earlier post transplant hematological recovery and less mucositis than MTX, with a similar incidence of GVHD. In this study we analyzed the post transplant outcomes of two cohorts of patients who underwent an HLA-identical sibling reduced intensity conditioning transplantation (allo-RIC) with GVHD prophylaxis consisting of CsA in combination with either MMF or a short course of MTX. We included 145 consecutive allo-RIC transplants performed between April 2000 and August 2007. The median follow-up for survivors was 41 months (4-105 months). The study group included 91 males. Median age was 55 years (range 18-71 years). Diagnoses included myeloid (n=65) and lymphoid (n=80) malignancies. GVHD prophylaxis consisted of CsA/MMF in 52 and CsA/MTX in 93 patients. The conditioning regimen was based on fludarabine in combination with BU (n=59) or melphalan (n=86). The occurrence of grade 2-4 mucositis was higher in the CsA/MTX group than in the CsA/MMF group (57 vs 23%, P=0.001). The cumulative incidence of acute and chronic GVHD was similar, 48 vs 50% and 71 vs 68%, respectively (P>0.7). The 2-year relapse and OS were similar in the CsA/MTX and CsA/MMF groups (29 vs 21%, P=0.3 and 52 vs 51%, P=0.7, respectively). Our results support further prospective studies comparing the use of the CsA/MMF combination with CsA/MTX as GVHD prophylaxis in HLA-identical sibling donor allo-RIC recipients.
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PMID:MTX or mycophenolate mofetil with CsA as GVHD prophylaxis after reduced-intensity conditioning PBSCT from HLA-identical siblings. 2014 24

Allogeneic stem cell transplantation (SCT) is the only therapeutic modality at present that may be delivered with curative intent in patients with myelodysplastic syndromes (MDS). Allogeneic CST replaces recipient dysplastic hemopoiesis with healthy donor haemopoiesis and immune system with an attendant graft-versus-leukemia (GvL) effect. Its applicability, however, is limited by the age of MDS patients, high rates of transplant-related mortality (TRM) and availability of a suitable HLA-matched donor. Results from several large centres indicated 3-year overall survival (OS) rates of 20-45%, which are almost equal with the results obtained by intensive chemotherapy alone. Failure was due primarily to TRM in patients with low-risk MDS and to disease recurrence in patients with high-risk MDS. Allogeneic SCT from matched unrelated donors produce poorer results than matched related siblings' transplantations. In an attempt to reduce TRM and deliver allogeneic SCT in a greater subgroup of MDS patients, many researchers used reduced-intensity allografts (RIC or "mini"-allograft) for MDS. Although differences in patient populations, preparative regimens, and graft-versus-host disease (GvHD) prophylaxis, as well as donor source (related vs. unrelated) have to be considered, OS of up to 40% at 3 years and disease-free survival (DFS) rates of almost 35% at 3 years have been reported in selected centres. However, randomized prospective studies are needed to further address the optimal choice of transplant conditioning intensity in MDS. Autologous SCT has been extremely investigated in MDS. It is limited to patients who have achieved a complete remission (CR), can be harvested, and are candidates for the procedure. Autologous SCT after successful induction chemotherapy may increase the proportion of long-term survivors, thus improving CR duration in some patients with MDS, particularly in younger patients in remission. Results for older patients are unsatisfactory. The relapse rate is up to 75%, with a 2-year probability of DFS of only 25% for patients 40-60 years of age. Therefore, there is very limited enthusiasm for the future of autologous SCT in the management of MDS patients.
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PMID:Transplantation strategies for the management of patients with myelodysplastic syndromes. 2014 43


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