Publications

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    ABSTRACT: Genomic studies have identified somatic alterations in the majority of myeloproliferative neoplasms (MPN) patients, including JAK2 mutations in the majority of MPN patients and CALR mutations in JAK2-negative MPN patients. However, the role of JAK-STAT pathway activation in different MPNs, and in patients without JAK2 mutations, has not been definitively delineated. We used expression profiling, SNP arrays, and mutational profiling to investigate a well-characterized cohort of MPN patients. MPN patients with homozygous JAK2V617F mutations were characterized by a distinctive transcriptional profile. Notably, a transcriptional signature consistent with activated JAK2 signaling is seen in all MPN patients regardless of clinical phenotype or mutational status. In addition, the activated JAK2 signature was present in patients with somatic CALR mutations. Conversely, we identified a gene expression signature of CALR mutations; this signature was significantly enriched in JAK2-mutant MPN patients consistent with a shared mechanism of transformation by JAK2 and CALR mutations. We also identified a transcriptional signature of TET2 mutations in MPN patent samples. Our data indicate that MPN patients, regardless of diagnosis or JAK2 mutational status are characterized by a distinct gene expression signature with upregulation of JAK-STAT target genes, demonstrating the central importance of the JAK-STAT pathway in MPN pathogenesis.
    Blood 04/2014; 123(22). DOI:10.1182/blood-2014-02-554634 · 10.43 Impact Factor
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    ABSTRACT: High-dose chemotherapy with autologous stem cell transplantation (ASCT) remains standard of care for patients with multiple myeloma (MM). Outpatient transplantation can be an attractive option given wait times and costs associated with inpatient procedures. We initiated an outpatient transplant protocol in 2006. Patients were treated at a University hospital outpatient clinic open five days a week. The aim of this study was to investigate safety and cost effectiveness of the outpatient program. 91 patients were transplanted between 2006 and 2010. Most patients (77%) had Durie & Salmon stage III disease, 38% had one or more comorbidities. Seventy-six (84%) were hospitalized during the first 100 days mainly for febrile neutropenia (n=71). Overall survival at day 100 was 100%. No patient was admitted to the Intensive Care Unit. Risk factors for prolonged hospitalization (more than 7 days) were disease stage IIB or higher and age older than 60 years. The reduction of costs was 19'521 C$ per patient compared to an inpatient transplant. This resulted in annual savings of approximately C$ 740'000. In summary, outpatient ASCT in a week day clinic for patients with multiple myeloma appears safe and cost effective but is associated with a relatively high hospitalization rate.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2012; 19(4). DOI:10.1016/j.bbmt.2012.12.006 · 3.35 Impact Factor
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    ABSTRACT: Aging is characterized by clonal expansion of myeloid-biased hematopoietic stem cells and by increased risk of myeloid malignancies. Exome sequencing of three elderly females with clonal hematopoiesis, demonstrated by X-inactivation analysis, identified somatic TET2 mutations. Recurrence testing identified TET2 mutations in 10 out of 182 individuals with X-inactivation skewing. TET2 mutations were specific to individuals with clonal hematopoiesis without hematological malignancies and were associated with alterations in DNA methylation.
    Nature Genetics 09/2012; 44(11):1179-1181. DOI:10.1038/ng.2413 · 29.65 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2012; 18(2):S262-S263. DOI:10.1016/j.bbmt.2011.12.173 · 3.35 Impact Factor
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    ABSTRACT: Myelofibrosis (MF) is a clonal stem cell disorder characterized by cytopenias, splenomegaly, marrow fibrosis, and systemic symptoms due to elevated inflammatory cytokines. MF is associated with decreased survival. The quality of life of patients with MF is similar to other advanced malignancies. Allogeneic hematopoietic cell transplantation is a curative treatment, but is applicable to a minority of patients with MF. None of the conventional therapies are known to alter the natural history of the disease. Significant progress has been made in the last few years in the understanding of disease biology of MF. Discovery of the JAK2V617F mutation paved the way for drug discovery in MF, and the first JAK1/2 inhibitor, ruxolitinib, has been approved by FDA and Health Canada. Several other JAK1/2 inhibitors are at various stages of clinical development. As a consequence, the therapeutic landscape of MF is changing from a disease where no effective therapies existed to one with several novel treatment options on the horizon. In this report, we assess the changing therapeutic options for MF, and critically analyze the position of novel treatments in the current armamentarium.
    01/2012; 2(3):170-86.
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    ABSTRACT: Autologous stem cell transplantation (ASCT) prolongs survival in patients with relapsed follicular lymphoma. ASCT is usually not curative, however. Myeloablative allogeneic transplantation has produced long-term survival at a cost of significant transplantation-related mortality (TRM), whereas reduced-intensity transplantation entails less TRM but has a higher relapse rate. We thus initiated a protocol consisting of ASCT followed by nonmyeloablative allogeneic transplantation (NMT) for relapsed follicular lymphoma to mimic myeloablative allogeneic transplantation without the associated toxicity. The NMT was non-T cell-depleted, and all donors were HLA-identical siblings. We report results in 27 patients with a median age of 49 years (range, 34-65 years). Five patients demonstrated histological progression toward an aggressive lymphoma. The patients had received a median of 3 lines of previous therapy. Disease status before ASCT included 8 patients in complete remission, 14 in partial remission, and 5 refractory. Five patients developed grade II-IV acute graft-versus-host disease, and 20 patients developed chronic graft-versus-host disease requiring systemic therapy. With a median follow-up of 39 months after NMT, overall survival and progression-free survival were 96% at 3 years. We conclude that the combined ASCT-NMT strategy appears to be safe, with excellent progression-free survival even in refractory and transformed cases. This novel approach warrants further investigation in larger prospective studies.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2011; 18(6):951-7. DOI:10.1016/j.bbmt.2011.11.028 · 3.35 Impact Factor
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    ABSTRACT: Data from a number of cohorts indicate that eosinophilia (Eo) could be associated with better outcomes following allogeneic hematopoietic cell transplant (HCT). However, little is known about its significance and prognostic value in chronic graft-versus-host disease (cGVHD) after nonmyeloablative (NMA) transplantation. Data were collected from 170 patients who underwent HCT using the same preparative regimen and GVHD prophylaxis. Donors were 6/6 HLA-matched siblings and stem cell source was peripheral blood. An eosinophil count of ≥0.5 × 10(9)/L was defined as Eo. Patients were transplanted mainly for lymphoproliferative disorders. Median age and follow-up were 54 years and 58 months, respectively. Incidents of grade II-IV acute GVHD (aGVHD) and cGVHD were 8.2% and 81.2%. Median time from HCT to cGVHD diagnosis was 142 days. Organs involved were: mouth in 80% of patients, skin in 75%, liver in 57%, eyes in 37%, gut in 14%, lungs in 5%, others in 5%. Eo was found in 44% of patients at diagnosis of cGVHD (range: 0.5-4.4 × 10(9)/L). Median time between first appearance of Eo and diagnosis of cGVHD was 4.5 days. We found no correlation between organ involvement and Eo but a lower prevalence of Eo in cGVHD associated with thrombocytopenia (P = .023). Nevertheless, we observed no association among Eo and overall survival (OS), relapse incidence, or nonrelapse mortality (NRM) in the overall cohort, nor in subsets of patients with multiple myeloma and follicular non-Hodgkin lymphoma. Although Eo is observed frequently in cGVHD following NMA transplantation, we report no correlation beween Eo and outcome.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2011; 17(11):1673-8. DOI:10.1016/j.bbmt.2011.04.012 · 3.35 Impact Factor
  • Bone marrow transplantation 03/2011; 47(2):294-5. DOI:10.1038/bmt.2011.44 · 3.47 Impact Factor
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    ABSTRACT: Hematopoietic stem cells (HSCs) replicate (self-renew) to create 2 daughter cells with capabilities equivalent to their parent, as well as differentiate, and thus can both maintain and restore blood cell production. Cell labeling with division-sensitive markers and competitive transplantation studies have been used to estimate the replication rate of murine HSCs in vivo. However, these methods are not feasible in humans and surrogate assays are required. In this report, we analyze the changing ratio with age of maternal/paternal X-chromosome phenotypes in blood cells from females and infer that human HSCs replicate on average once every 40 weeks (range, 25-50 weeks). We then confirm this estimate with 2 independent approaches, use the estimate to simulate human hematopoiesis, and show that the simulations accurately reproduce marrow transplantation data. Our simulations also provide evidence that the number of human HSCs increases from birth until adolescence and then plateaus, and that the ratio of contributing to quiescent HSCs in humans significantly differs from mouse. In addition, they suggest that human marrow failure, such as the marrow failure that occurs after umbilical cord blood transplantation and with aplastic anemia, results from insufficient numbers of early progenitor cells, and not the absence of HSCs.
    Blood 02/2011; 117(17):4460-6. DOI:10.1182/blood-2010-08-303537 · 10.43 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2011; 17(2). DOI:10.1016/j.bbmt.2010.12.455 · 3.35 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2010; 24(9):1656-7. DOI:10.1038/leu.2010.144 · 9.38 Impact Factor
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    ABSTRACT: Background / Purpose: Cytomegalovirus (CMV) is the most important viral pathogen in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. Pre-emptive therapy has become the most commonly used strategy to prevent CMV disease after allogeneic HSCT and the use of a very effective pre-emptive antiviral agent could theoretically minimize the risk of CMV disease as well as abrogate prospective surveillance after allogeneic HSCT. Valacyclovir (VAL) is rapidly and extensively converted to acyclovir after oral administration, resulting in a 3- to 5-fold increased acyclovir bioavailability when compared with oral acyclovir, and conferring potential antiviral activity against CMV and other herpesviridae. We conducted a prospective randomized study based on the hypothesis that universal prophylaxis with VAL until D+100 after allogeneic HSCT in recipients at high risk of CMV reactivation would lead to a decreased incidence of CMV viremia as well as other herpesviridae reactivation. Main conclusion: We found that VAL prophylaxis is effective in preventing CMV, HSV and EBV reactivation after allogeneic HSCT. Further larger studies are needed to discover the optimal use of VAL in allogeneic HSCT recipients.
    51st American Society of Hematology Annual Meeting 2009; 03/2010
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    Blood 09/2009; 114(11):2358-2359. DOI:10.1182/blood-2009-06-226035 · 10.43 Impact Factor
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    Bone marrow transplantation 09/2009; 45(5):953-4. DOI:10.1038/bmt.2009.246 · 3.47 Impact Factor
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    ABSTRACT: Incidence of grade II-IV acute graft-versus-host disease (aGVHD) in nonmyeloablative (NMA) transplant recipients remains high. To date, the ideal prophylaxis regimen, which minimizes aGVHD and chronic GVHD (cGVHD), but does not abrogate graft-versus-tumor (GVT) response, has not been described. Because tacrolimus is more potent than cyclosporine (CSA), and because mycophenolate mofetil (MMF) is an effective immunosuppressant that does not lead to mucositis, we hypothesized that a combination of these 2 oral agents may be an effective GVHD prophylactic strategy. We, therefore, designed an outpatient prospective cohort study with a conditioning regimen consisting of fludarabine (Flu) 30 mg/m2 daily and cyclophosphamide (Cy) 300 mg/m2 daily for 5 days followed by infusion of blood stem cells. Tacrolimus 3mg twice a day was started on day (D) -8, adjusted to achieve levels 10-15 nmol/L, continued until D +50 and then tapered by D +100 or +180 according to estimated risk of relapse. MMF 1000 mg twice a day was started on D +1 and discontinued on D +50. To date, 131 patients (males/females: 75/56) with a median age of 54 years have received a 6/6 matched sibling transplant using this protocol. Indication for NMA transplant included age >55 years (24%), expected increased risk of toxicity (28%), or participation in a multiple myeloma (MM) sequential protocol (48%). Most common diagnoses included MM (N = 62), non-Hodgkin lymphoma (NHL, N = 46), and acute leukemia (N = 10). Following infusion of 6.8 x 10(6) CD34+ cells/kg (range: 0.30-22.3), neutrophil and lymphocyte engraftment occurred in 95% of patients by D +180. The estimated cumulative incidence of classical grade I-IV aGVHD by D +120 was 11.6% (95% confidence interval [CI]: 7.1-18.5). No grade IV aGVHD was observed. In addition, 15 patients (12%: CI: 7.4-19.2; median D +140) developed an overlap syndrome consisting of clinical and histologic features of both aGVHD and cGVHD simultaneously. The estimated cumulative incidence of extensive cGVHD was 76.1% (95% CI: 67.4-83.9) at 2 years, with clinical features at presentation similar to other reported series. In patients developing extensive cGVHD, the probability of remaining on immunosuppression at 5 years was 34.8% (95% CI: 16.4-57.3). With a median follow-up of 982 days, the estimated probabilities of nonrelapse mortality (NRM) and overall survival (OS) were 15.5% (95% CI: 9.0-26.1) and 62.7% (95% CI: 51.4-72.1). The cumulative incidence of relapse was 30% at 7 years. Following NMA transplant, disease-free survival (DFS) was highest in recipients with follicular NHL (79.8%: 95% CI: 57.6-91.2) and lowest in large cell NHLs (34.3%: 95% CI: 1.6-75.9). From this large group of patients treated with a uniform conditioning and GVHD prophylaxis regimen, we conclude that aGVHD prophylaxis with early use of tacrolimus and MMF is safe, effective, and associated with low NRM. Future strategies will need to focus on decreasing the incidence of extensive cGVHD without increasing the risk of relapse.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 08/2009; 15(8):919-29. DOI:10.1016/j.bbmt.2009.04.004 · 3.35 Impact Factor
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    ABSTRACT: BACKGROUND: Telomeres play a crucial role in maintaining the physical integrity of chromosomes. Telomere length (TL) is severely reduced in individuals with dyskeratosis congenita and a number of other bone marrow failure syndromes. The TL of healthy individuals is highly variable, but shortens with age. It is presently unclear if variations in TL observed in normal aging individuals affect significantly their hematopoietic reserve. Method We studied the correlation between leukocyte age-adjusted TL (aTL) and blood cell parameters (total leukocytes, neutrophils, monocytes, eosinophils, lymphocytes, hemoglobin, and platelets) in a large cohort (n=717) of women aged 38-100 years. Result We did not find any significant correlation between aTL and blood counts. CONCLUSION: Our data suggest that the aTL of aging individuals is not significantly predictive of their hematopoietic reserve, which implies that TL measurement may not be clinically useful in the selection of hematopoietic stem cell transplantation donors.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2009; 64(9):965-7. DOI:10.1093/gerona/glp065 · 4.98 Impact Factor
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    ABSTRACT: Nonrandom X-chromosome inactivation (XCI), also known as skewing, has been documented in the blood cells of a significant proportion of normal aging women by the use of methylation-based assays at the polymorphic human androgen receptor locus (HUMARA). Recent data obtained with a new transcription-based XCI determination method, termed suppressive polymerase chain reaction (PCR), has shed controversy over the validity of XCI ratio results obtained with HUMARA. To resolve this disparity, we analyzed XCI in polymorphonuclear leukocytes of a large cohort of women aged 43 to 100 years with the use of HUMARA (n=100), a TaqMan single nucleotide polymorphism (SNP) assay (n=90), and the suppressive polymerase chain reaction (PCR) assay (n=67). The 3 methods yielded similar skewing incidences (42%, 38%, and 40%, respectively), and highly concordant XCI ratios. This confirms that the skewing of XCI ratio seen in blood cells of aging women is a bona fide and robust biologic phenomenon.
    Blood 03/2009; 113(15):3472-4. DOI:10.1182/blood-2008-12-195677 · 10.43 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2009; 15(2):19-19. DOI:10.1016/j.bbmt.2008.12.057 · 3.35 Impact Factor
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    Bone marrow transplantation 02/2009; 44(2):131-2. DOI:10.1038/bmt.2008.439 · 3.47 Impact Factor
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    ABSTRACT: As a key component of the transforming growth factor-beta (TGF-beta) pathway, SMAD3 plays an essential role in development and maintenance of self-tolerance. Furthermore, a recent study based on gene-expression profiling in donors of allogeneic hematopoietic cell grafts revealed that the level of expression of several components of the TGF-beta pathway can predict the occurrence of graft-versus-host disease (GVHD) in recipients. The gene with the best GVHD predictive accuracy was SMAD3: no recipients suffered from GVHD when their donor cells expressed high levels of SMAD3 transcripts. The present study had two specific aims: to validate differential expression of SMAD3 transcripts in an independent and larger cohort of subjects and to determine whether interindividual differences were dictated by cis-acting genetic elements. In a cohort of 397 subjects, we found that SMAD3 transcript levels varied over a sixfold range. Analyses of SMAD3 single nucleotide polymorphisms and of SMAD3 promoter methylation patterns provide compelling evidence that interindividual differences in SMAD3 transcript levels do not result from in-cis genetic variations. Of note, part of the variance in SMAD3 expression was gender related as women expressed lower levels of SMAD3 transcripts than men.
    Genes and immunity 02/2009; 10(2):192-6. DOI:10.1038/gene.2008.101 · 3.79 Impact Factor

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