LATE EFFECTS OF HEMATOPETIC STEM CELL TRANSPLANTATION Impact of chronic GVHD on late complications after hematopoietic cell transplantation

Current results with transplantation of marrow or blood derived hemopoietic stem cells (HCT) in patients with aplastic anemia and patients who do not develop chronic graft-versus-host disease (GVHD) show life expectancies similar to agematched controls. However, patients with advanced malignant diseases and patients who develop chronic GVHD after transplant are at risk of late disease recurrence and delayed, potentially fatal complications Infections Late infections due to bacterial, viral and fungal organisms occur most commonly in patients with chronic GVHD. Early post-transplant prophylaxis may result in an increased incidence of late infections (see e.g., acyclovir/ganciclovir and late CMV infections). It is standard practice to give prophylaxis for infections caused by Pneumocystis carinii, varicella zoster and encapsulated bacteria (and, more recently, fungal organisms) during the first year post-transplant, or longer, for patients with chronic GVHD. Airway and pulmonary disease The bronchial tree may be involved by GVHD The pathogenesis of air flow obstruction (AFO) after HCT is not fully understood Progressive bronchiolitis obliterans has been reported to occur in 10% of all patients with chronic GVHD [6] from 3 months to 2 years after HCT. Clinical and pathological findings are similar to those seen after lung or heart-lung transplants A recent analysis of results in 6523 patients transplanted at FHCRC revealed 51 cases of bronchiolitis obliterans organizing pneumonia (BOOP), all but two after allogeneic transplants. BOOP was diagnosed at 5 Á/2,819 (median 108) days after HCT. The disease was significantly associated with acute and chronic GVHD. The disease progressed in 22% of patients and resolved or was stable in the remaining patient

Tumor Necrosis Factor Polymorphism Affects Transplantation Outcome in Patients with Myelodysplastic Syndrome but Not in Those with Chronic Myelogenous Leukemia, Independent of the Presence of HLA-DR15

Both the presence of HLA-DR15 and tumor necrosis factor (TNF)-α levels have been reported to affect outcome after hematopoietic cell transplantation (HCT). Patients with a myelodysplastic syndrome (MDS) show a high prevalence of HLA-DR15 and express high levels of TNF-α in the bone marrow. The present analysis involving 7950 patients showed an HLA-DR15 frequency of 31% in patients with MDS, compared with only 23% in patients with chronic myelogenous leukemia (CML). HLA-DR15 was more prevalent in Caucasian patients than in non-Caucasian patients (P = .01). The numbers of patients in the non-Caucasian subgroups were too small to allow further analysis. Among Caucasian patients with MDS and CML, the presence of HLA-DR15 did not significantly affect the occurrence of graft-versus-host disease, relapse, nonrelapse mortality (NRM), or survival. However, there was a significant correlation between DR15 and TNF polymorphisms at position -308 among patients with MDS, and the TNF-308 AG genotype conferred an increased risk of NRM compared with the GG genotype (hazard ratio [HR], 1.49; P = .02), even after adjusting for DR15. Conversely, the TNF-863 AA genotype was correlated with decreased overall mortality and NRM compared with the CC genotype (HR, 0.36, P = .04 vs HR, 0.13, P = .04), even after adjusting for DR15. There was no significant association between TNF-308 or -863 polymorphisms and transplantation outcome in CML patients. These results suggest that TNF polymorphisms, but not DR15, affect transplantation outcome in a disease-dependent manner

Gene Expression Patterns in Myelodyplasia Underline the Role of Apoptosis and Differentiation in Disease Initiation and Progression

The myelodysplastic syndromes (MDS) are clonal stem cell disorders, characterized by ineffective and dysplastic hematopoiesis. The genetic and epigenetic pathways that determine disease stage and progression are largely unknown. In the current study we used gene expression microarray methodology to examine the gene expression differences between normal hematopoietic cells and hematopoietic cells from patients with MDS at different disease stages, using both unselected and CD34+ selected cells. Significant differences between normal and MDS hematopoietic cells were observed for several genes and pathways. Several genes promoting or opposing apoptosis were dysregulated in MDS cases, most notably MCL1 and EPOR. Progression from RA to RAEB(T) was associated with increased expression of several histone genes. In addition, the RAR-RXR pathway, critical for maintaining a balance between self-renewal and differentiation of hematopoietic stem cells, was found to be deregulated in hematopoietic cells from patients with advanced MDS compared to patients with refractory anemia. These findings provide new insights into the understanding of the pathophysiology and progression of MDS, and may guide to new targets for therapy. Taken together with previous published data, the present results also underscore the considerable complexity of the regulation of gene expression in MDS

Pretransplant neutropenia is associated with poor-risk cytogenetic features and increased infection-related mortality in patients with myelodysplastic syndromes.

A retrospective cohort analysis was performed to determine the impact of neutropenia on the outcome of hematopoietic cell transplantation (HSCT) in patients with myelodysplasia (MDS). Among 291 consecutive patients, 178 (61%) had absolute neutrophil counts (ANCs) or =1500/microL within 2 weeks before HSCT. Neutropenic patients more often had poor-risk karyotypes (34% versus 12%, P < .0001) and high-risk International Prognostic Scoring System scores (37% versus 18%, P = .0006). After HSCT, the rate of infections caused by Gram-positive bacteria and invasive fungal infections was significantly increased among neutropenic patients (rate ratio [RR] 1.77, P = .02 and RR = 2.56, P = .03, respectively), whereas infections caused by Gram-negative bacteria were not affected (RR 1.33, P = .53). The hazards of nonrelapse mortality (NRM) (hazard ratio [HR] = 1.62 [1.1-2.4], P = .01), overall mortality (HR = 1.55 [1.1-2.1], P = 0.007), and infection-related mortality (HR = 2.22 [1.2-4.2], P = .01) were increased in neutropenic patients, whereas relapse, engraftment, and graft-versus-host-disease were not affected. After adjusting for cytogenetic risk and marrow myeloblast percentages, neutropenic patients remained at significant hazard for infection-related mortality (HR = 1.94 [1.0-3.8], P = .05), but not for overall mortality or NRM. We propose that intensified strategies to prevent infections should be implemented in MDS patients with preexisting neutropenia who undergo HSCT

Therapy with mycophenolate mofetil for refractory acute and chronic GVHD.

We evaluated the pharmacokinetics and efficacy of oral mycophenolate mofetil (MMF) for treatment of refractory GVHD. In a prospective study of acute GVHD, 9 of 19 patients (47%) had a response and 10 (53%) had no improvement. Survival at 6 and 12 months after the start of MMF was 37 and 16%, respectively. In a retrospective study of acute GVHD, 14 of 29 patients (48%) had a response and 15 (52%) had no improvement. Survival at 6 and 12 months was 55 and 52%, respectively. In a prospective study of chronic GVHD, the cumulative incidence of disease resolution and withdrawal of all systemic immunosuppressive treatment was 9, 17 and 26% at 12, 24 and 36 months, respectively, after starting MMF. Thirteen patients (59%) required additional systemic immunosuppressive treatment for chronic GVHD. Nine of the 42 patients (21%) in the prospective studies discontinued MMF treatment because of toxicity. The area under the curve plasma concentrations of mycophenolic acid seemed to be suboptimal among patients with acute GVHD but not among those with chronic GVHD. MMF can be used effectively for treatment of GVHD.Bone Marrow Transplantation advance online publication, 20 April 2009; doi:10.1038/bmt.2009.76

Conditioning intensity and peritransplant flow cytometric MRD dynamics in adult AML

In acute myeloid leukemia (AML), measurable residual disease (MRD) before or after allogeneic hematopoietic cell transplantation (HCT) is an established independent indicator of poor outcome. To address how peri-HCT MRD dynamics could refine risk assessment across different conditioning intensities, we analyzed 810 adults transplanted in first or second remission after myeloablative conditioning (MAC; n = 515) or non-MAC (n = 295) who underwent multiparameter flow cytometry–based MRD testing before as well as 20 to 40 days after allografting. Patients without pre- and post-HCT MRD (MRDneg/MRDneg) had the lowest risks of relapse and highest relapse-free survival (RFS) and overall survival (OS). Relative to those patients, outcomes for MRDpos/MRDpos and MRDneg/MRDpos patients were poor regardless of conditioning intensity. Outcomes for MRDpos/MRDneg patients were intermediate. Among 161 patients with MRD before HCT, MRD was cleared more commonly with a MAC (85 of 104; 81.7%) than non-MAC (33 of 57; 57.9%) regimen (P = .002). Although non-MAC regimens were less likely to clear MRD, if they did, the impact on outcome was greater. Thus, there was a significant interaction between conditioning intensity and “MRD conversion” for relapse (P = .020), RFS (P = .002), and OS (P = .001). Similar findings were obtained in the subset of 590 patients receiving HLA-matched allografts. C-statistic values were higher (indicating higher predictive accuracy) for peri-HCT MRD dynamics compared with the isolated use of pre-HCT MRD status or post-HCT MRD status for prediction of relapse, RFS, and OS. Across conditioning intensities, peri-HCT MRD dynamics improve risk assessment over isolated pre- or post-HCT MRD assessments in patients with AML

Conditioning Intensity, Pre-Transplant Flow Cytometric Measurable Residual Disease, and Outcome in Adults with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

How conditioning intensity is related to outcomes of AML patients undergoing allografting in morphologic remission is an area of great ongoing interest. We studied 743 patients in morphologic remission and known pre-transplant measurable residual disease (MRD) status determined by multiparameter flow cytometry (MFC) who received a first allograft after myeloablative, reduced intensity, or nonmyeloablative conditioning (MAC, RIC, and NMA). Overall, relapse-free survival (RFS) and overall survival (OS) were longer after MAC than RIC or NMA conditioning, whereas relapse risks were not different. Among MRD(pos)patients, 3-year estimates of relapse risks and survival were similar across conditioning intensities. In contrast, among MRD(neg)patients, 3-year RFS and OS were longer for MAC (69% and 71%) than RIC (47% and 55%) and NMA conditioning (47% and 52%). Three-year relapse risks were lowest after MAC (18%) and highest after NMA conditioning (30%). Our data indicate an interaction between conditioning intensity, MFC-based pre-transplant MRD status, and outcome, with benefit of intensive conditioning primarily for patients transplanted in MRD(neg)remission. Differing from recent findings from other studies that indicated MAC is primarily beneficial for some or all patients with MRD(pos)pre-HCT status, our data suggest MAC should still be considered for MRD(neg)AML patients if tolerated