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ABSTRACT: BACKGROUND: Transformed non-Hodgkin's lymphoma arising from follicular lymphoma (TL) carries a poor prognosis with a median survival time after transformation reported to be approximately 1 year. PATIENTS AND METHODS: Fifty-one consecutive patients with TL received SCT between January 2000 and December 2010 (autologous SCT, n = 44, allogeneic SCT, n = 7). RESULTS: Thirty-six (70.5%) patients had an early transformation, defined as histologic evidence of transformation at the time of initial diagnosis or transformation within 1 year of follicular lymphoma. Fifteen patients had early stage disease (29%) and 36 (71%) had advanced stage disease on presentation. At the time of analysis, 37 patients were alive with an estimated 5-year overall survival (OS) and event free survival (EFS) of 61.8% and 45%, respectively. OS and EFS were not significantly different between types of transplant procedure. The major cause of transplant failure was disease recurrence, with estimated 2-year relapse rate of 37.4%. Importantly, early transformation was independently associated with improved OS (hazard ratio [HR] 3.29; P = .028) and EFS (HR 2.49; P = .029). CONCLUSION: Our results indicate that an aggressive transplant approach should be considered first in patients with TL and emphasize the need to incorporate novel strategies (eg, immunomodulation) early post-SCT to prevent relapses as disease recurrence remains the major cause of failure in heavily pretreated patients.
Clinical lymphoma, myeloma & leukemia 09/2012;
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ABSTRACT: Measurement of minimal residual disease is routine in diseases such as chronic myelogenous leukemia, precursor B cell acute lymphoblastic leukemia, and acute promyelocytic leukemia because it provides important prognostic information. However, the role of minimal residual disease testing has not been widely adopted in multiple myeloma (MM), with other parameters such as the International Staging System (ISS) and cytogenetic analysis primarily guiding therapy and determination of prognosis. Until recently, achieving a complete response (CR), as defined by the International Myeloma Working Group (IMWG) criteria, was rare in patients with MM. The use of novel agents with or without autologous peripheral blood stem cell transplantation (auto-PBSCT) has significantly increased CR rates, thus increasing overall survival (OS) rates. The majority of patients with MM have persistent levels of residual disease that are below the sensitivity of bone marrow (BM) morphology, protein electrophoresis with immunofixation, and light chain quantitation even after attaining CR and will eventually relapse. Measurement of minimal residual disease by more sensitive methods, and the use of these methods as a tool for predicting patient outcomes and guiding therapeutic decisions, has thus become more relevant. Methods available for monitoring minimal residual disease in MM include PCR and multiparameter flow cytometry (MFC), both of which have been shown to be valuable in other hematologic malignancies; however, neither has become a standard of care in MM. Here, we review current evidence for using minimal residual disease measurement for risk assessment in MM as well as incorporating pretreatment factors and posttreatment minimal residual disease monitoring as a prognostic tool for therapeutic decisions, and we outline challenges to developing uniform criteria for minimal residual disease monitoring.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2012; · 3.15 Impact Factor
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Nishitha Reddy,
John P Greer,
Stacey Goodman,
Adetola Kassim,
David S Morgan,
Wichai Chinratanalab,
Stephen Brandt,
Brian Englehardt,
Olalekan Oluwole, Madan H Jagasia,
Bipin N Savani
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ABSTRACT: Intensive induction regimen followed by high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) is frequently used to improve outcomes in patients with mantle-cell lymphoma. The comparative impact of conventional vs intensive induction regimen before transplantation is unknown. Forty-eight patients with mantle-cell lymphoma receiving SCT at our institution between January 2000 and December 2010 were included in this study. At the time of initial presentation, 43 (89.5%) had stage IV disease and 18 (37.5%) received more than one chemotherapy regimen before transplantation. Forty patients underwent auto-SCT and 7 had allogeneic SCT (allo-SCT); 1 patient had an allo-SCT for relapsed disease after auto-SCT. At the time of this analysis (median follow-up of 6 years from diagnosis and 4 years from transplantation), 40 patients (88%) were alive with a 5-year disease-free survival of 74.8%. Age, disease stage, number of regimens pre-SCT, pre-SCT disease status, and type of SCT had no impact on long-term outcomes. Importantly, there were no differences among the types of induction regimen on outcomes in this cohort receiving SCT. Based on our data, we believe that future studies should focus on strategies to prevent disease relapse rather than comparing induction regimens before stem cell transplantation.
Experimental hematology 01/2012; 40(5):359-66. · 3.11 Impact Factor
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ABSTRACT: As survival rates continue to increase after allogeneic stem cell transplant (allo-SCT), the associated long-term complications of transplant need to be taken into consideration. Here, we review the endocrine and metabolic complications associated with transplant survivors, including diabetes, dyslipidemia, hypertension, cardiovascular disease, hypogonadism, vitamin D deficiency, osteoporosis, thyroid disease, adrenal dysfunction, and pituitary disorders, and provide a brief summary of evaluation and treatment of these conditions.
Seminars in Hematology 01/2012; 49(1):66-72. · 3.99 Impact Factor
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Yoshihiro Inamoto,
Xiaoyu Chai,
Brenda F Kurland,
Corey Cutler,
Mary E D Flowers,
Jeanne M Palmer,
Paul A Carpenter,
Mary J Heffernan,
David Jacobsohn, Madan H Jagasia,
Joseph Pidala,
Nandita Khera,
Georgia B Vogelsang,
Daniel Weisdorf,
Paul J Martin,
Steven Z Pavletic,
Stephanie J Lee
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ABSTRACT: To validate measurement scales for rating ocular chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. Candidate scales were recommended for use in clinical trials by the National Institutes of Health (NIH) Chronic GVHD Consensus Conference or have been previously validated in dry eye syndromes.
Prospective follow-up study.
Between August 2007 and June 2010, the study enrolled 387 patients with chronic GVHD in a multicenter, prospective, observational cohort.
Using anchor-based methods, we compared clinician or patient-reported changes in eye symptoms (8-point scale) with calculated changes in 5 candidate scales: The NIH eye score, patient-reported global rating of eye symptoms, Lee eye subscale, Ocular Surface Disease Index, and Schirmer test. Change was examined for 333 follow-up visits where both clinician and patient reported eye involvement at the previous visit. Linear mixed models were used to account for within-patient correlation.
An 8-point scale of clinician or patient-reported symptom change was used as an anchor to measure symptom changes at the follow-up visits.
In serial evaluations, agreement regarding improvement, stability, or worsening between the clinician and patient was fair (weighted kappa = 0.34). Despite only fair agreement between evaluators, all scales except the Schirmer test correlated with both clinician-reported and patient-reported changes in ocular GVHD activity. Among all scales, changes in the NIH eye scores showed the greatest sensitivity to symptom change reported by clinicians or patients.
Our results support the use of the NIH eye score as a sensitive measure of eye symptom changes in clinical trials assessing treatment of chronic GVHD.
Ophthalmology 12/2011; 119(3):487-93. · 5.45 Impact Factor
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William B Clark,
Kristin D Brown-Gentry,
Dana C Crawford,
Kang-Hsien Fan,
Jennifer Snavely,
Heidi Chen,
Bipin N Savani,
Adetola Kassim,
John P Greer,
Friedrich G Schuening,
Brian G Engelhardt, Madan H Jagasia
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ABSTRACT: B-cell activating factor (BAFF) single nucleotide polymorphisms (SNPs) are associated with autoimmune diseases. Because patients with classic and overlap chronic GVHD (cGVHD) have features of autoimmune diseases, we studied the association of recipient and/or donor BAFF SNPs with the phenotype of GVHD after allogeneic stem cell transplantation. Twenty tagSNPs of the BAFF gene were genotyped in 164 recipient/donor pairs. GVHD after day 100 occurred in 124 (76%) patients: acute GVHD (aGVHD) subtypes (n = 23), overlap GVHD (n = 29), and classic cGVHD (n = 72). In SNP analyses, 9 of the 20 tag SNPs were significant comparing classic/overlap cGVHD versus aGVHD subtypes/no GVHD. In multivariate analyses, 4 recipient BAFF SNPs (rs16972217 [odds ratio = 2.72, P = .004], rs7993590 [odds ratio = 2.35, P = .011], rs12428930 [odds ratio2.53, P = .008], and rs2893321 [odds ratio = 2.48, P = .009]) were independent predictors of GVHD subtypes, adjusted for conventional predictors of cGVHD. This study shows that genetic variation of BAFF modulates GVHD phenotype after allogeneic stem cell transplantation.
Blood 05/2011; 118(4):1140-4. · 9.90 Impact Factor
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Claudio G Brunstein,
Ephraim J Fuchs,
Shelly L Carter,
Chatchada Karanes,
Luciano J Costa,
Juan Wu,
Steven M Devine,
John R Wingard,
Omar S Aljitawi,
Corey S Cutler, Madan H Jagasia,
Karen K Ballen,
Mary Eapen,
Paul V O'Donnell
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ABSTRACT: The Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603).
Blood 04/2011; 118(2):282-8. · 9.90 Impact Factor
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ABSTRACT: By using flow cytometry, we analyzed myeloid nuclear differentiation antigen (MNDA) expression in myeloid precursors in bone marrow from patients with myelodysplastic syndrome (MDS) and control samples from patients undergoing orthopedic procedures. The median percentage of MNDA-dim myeloid precursors in MDS cases was 67.4% (range, 0.7%-97.5%; interquartile range, 44.9%-82.7%) of myeloid cells, with bimodal MNDA expression in most MDS samples. Control samples demonstrated a median MNDA-dim percentage in myeloid precursors of 1.2% (range, 0.2%-13.7%; interquartile range, 0.6%-2.7%), with no bimodal pattern in most samples. The area under the receiver operating characteristic curve for MNDA-dim percentage in myeloid precursors was 0.96 (P = 9 × 10(-7)). Correlation of MNDA-dim levels with World Health Organization 2008 morphologic diagnoses was not significant (P = .21), but correlation with patient International Prognostic Scoring System scores suggested a trend (P = .07). Flow cytometric assessment of MNDA in myeloid precursors in bone marrow may be useful for the diagnosis of MDS.
American Journal of Clinical Pathology 03/2011; 135(3):380-5. · 2.60 Impact Factor
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ABSTRACT: Posttransplantation diabetes mellitus (PTDM) is a frequent complication after allogeneic stem cell transplantation (allo-SCT), important for its negative impact on cardiovascular health. Risk factors for PTDM are not well defined. We conducted a prospective study to investigate the risk factors and incidence for PTDM in the first 100 days after allo-SCT. A total of 84 patients completed the study, 60% of whom developed PTDM. In a multivariate logistic regression model, pretransplantation c-peptide level (>3.6 ng/mL; odds ratio [OR], 5.9; 95% confidence interval [CI], 1.77-20.22; P = .004), unrelated donor allo-SCT (OR, 4.3; 95% CI, 1.34-14.2; P = .014), and peak steroid dose >1 mg/kg/day (OR, 5.09; 95% CI, 1.19-23.2; P = .035) were identified as independent predictors of PTDM. In addition, overall survival (OS) was inferior in patients with PTDM compared with those without PTDM (mean survival, 2.26 years vs 2.7 years; P = .021). Pretransplantation c-peptide level greater than the cohort median (>3.6 ng/mL) also was associated with inferior OS (mean, 1.7 years vs 2.9 years; P = .012). In a multivariate Cox proportional hazards model, high-risk disease (hazard ratio [HR], 2.34; 95% CI, 1.09-5.28; P = .029) and pretransplantation c-peptide level >3.6 ng/mL (HR, 1.05; 95% CI, 1.01-1.09; P = .013) were independent predictors of OS when adjusted for systemic steroids and regimen intensity. We suspect that diabetes mellitus in the immediate posttransplantation period may be mediated via an inflammatory pathway that contributes to insulin resistance in the host adipose tissue. Our study is the first to report the risk factors of early PTDM in patients undergoing allo-SCT and identifies pretransplantation c-peptide as an independent predictor of diabetes and survival.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(1):86-92. · 3.15 Impact Factor
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ABSTRACT: Numerous methods exist for monitoring residual disease in multiple myeloma using peripheral blood, urine, and bone marrow (BM) techniques. This study was conducted in a cohort of 83 patients to compare residual disease detection using serum protein electrophoresis (SPE) and urine protein electrophoresis (UPE) with immunofixation with immunoperoxidase staining of BM tissue sections. Of the 83 patients, 49 had a positive SPE and/or UPE result and all had BM involvement shown by immunohistochemical analysis. The results for SPE and UPE were negative in 17 patients, and all 17 had a negative immunohistochemical BM result for a negative predictive value for SPE/UPE of 100%. In addition, SPE and UPE detected residual disease in 17 patients with negative BM biopsy studies. SPE and UPE can be used to screen patients for residual disease, and negative results for both can obviate the need for BM biopsy for the detection of residual disease by immunohistochemical analysis.
American Journal of Clinical Pathology 07/2010; 134(1):139-44. · 2.60 Impact Factor
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Madan H Jagasia,
Bipin N Savani,
George Stricklin,
Brian Engelhardt,
Adetola Kassim,
Sheri Dixon,
Heidi Chen,
Wichai Chinratanalab,
Stacey Goodman,
John P Greer,
Friedrich Schuening
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ABSTRACT: The National Institutes of Health (NIH) classification of graft-versus-host disease (GVHD) is a significant improvement over prior classifications, and has prognostic implications. We hypothesized that the NIH classification of GVHD would predict the survival of patients with GVHD treated with extracorporeal photopheresis (ECP). Sixty-four patients with steroid refractory/dependent GVHD treated with ECP were studied. The 3-year overall survival (OS) was 36% (95% confidence interval [CI] 13-59). Progressive GVHD was seen in 39% of patients with any acute GVHD (aGVHD) (classic acute, recurrent acute, overlap) compared to 3% of patients with classic chronic GVHD (cGVHD) (P=.002). OS was superior for patients with classic cGVHD (median survival, not reached) compared to overlap GVHD (median survival, 395 days, 95% CI 101 to not reached) and aGVHD (delayed, recurrent or persistent) (median survival, 72 days, 95% CI 39-152). In univariate analyses, significant predictors of survival after ECP included GVHD subtype, bilirubin, platelet count, and steroid dose. In multivariate analyses overlap plus classic cGVHD was an independent prognostic feature predictive of superior survival (hazard ratio [HR] 0.34, 95% CI 0.14-0.8, p=.014). This study suggests that NIH classification can predict outcome after ECP for steroid refractory/dependent GVHD.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2009; 15(10):1288-95. · 3.15 Impact Factor
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Brian G Engelhardt,
Derek W Holland,
Stephen J Brandt,
Wichai Chinratanalab,
Stacey A Goodman,
John P Greer, Madan H Jagasia,
Adetola A Kassim,
David S Morgan,
Katherine L Ruffner,
Friedrich G Schuening,
Steven Wolff,
Rhonda Bitting,
Paulgun Sulur,
Richard S Stein
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ABSTRACT: Between January 1990 and April 2001, 115 patients received high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) for relapsed or refractory Hodgkin lymphoma (HL). With a median follow-up of 58 months (range, 1 - 175 months), 5-year progression-free survival (PFS) and overall survival (OS) were 46% and 58%, respectively. Twelve patients with primary refractory disease had a 5-year PFS of 41% and OS of 58%, not significantly different from those of the remaining cohort. Early and overall regimen related mortality were 7% and 16%, respectively. Male gender (P = 0.04) and a time to relapse (TTR) < 12 months (P = 0.03) were associated with decreased OS by univariate analysis. In multivariate analysis, TTR < 12 months remained statistically significant (P = 0.04). We have confirmed that HDT and ASCT result in long-term survival for a proportion of patients with relapsed or refractory HL. All patients, including those with primary refractory disease, benefited from HDT and ASCT.
Leukemia and Lymphoma 09/2007; 48(9):1728-35. · 2.58 Impact Factor
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ABSTRACT: Reduced levels of human myeloid nuclear differentiation antigen (MNDA) gene transcripts have been detected in both familial and sporadic cases of myelodysplastic syndromes (MDS). Numerous reports implicate elevated apoptosis/programmed cell death and death ligands and their receptors in the pathogenesis of MDS. MNDA and related proteins contain the pyrin domain that functions in signaling associated with programmed cell death and inflammation. We tested the hypothesis that MNDA is involved in the regulation of programmed cell death in human myeloid hematopoietic cells. Clones of K562 cells (MNDA-null) that expressed ectopic MNDA protein were established using retroviral transduction. MNDA-expressing K562 clones were resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis, but were not protected from programmed cell death induced with genotoxic agents or H(2)O(2). MNDA protein expression assessed in control and intermediate and high-grade MDS marrows showed several patterns of aberrant reduced MNDA. These variable patterns of dysregulated MNDA expression may relate to the variable pathophysiology of MDS. We propose that MNDA has a role regulating programmed cell death in myeloid progenitor cells, and that its down-regulation in MDS is related to granulocyte-macrophage progenitor cell sensitivity to TRAIL-induced programmed cell death.
Cancer Research 06/2006; 66(9):4645-51. · 7.86 Impact Factor
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Edward R Arrowsmith,
William R Macon,
Marsha C Kinney,
Richard S Stein,
Stacey A Goodman,
David S Morgan,
John M Flexner,
John B Cousar, Madan H Jagasia,
Thomas L McCurley,
John P Greer
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ABSTRACT: The purpose of this study was to better define the clinical features and natural history of peripheral T-cell lymphomas (PTCL) entities included in the Revised European American lymphoma (REAL) classification. Cases of PTCL were retrieved from the records of the Department of Pathology and classified according to the REAL classification. In addition, cases of anaplastic large cell lymphoma (ALCL) were divided into classical, small cell, and primary cutaneous subtypes, and immunostaining for the anaplastic large-cell kinase (ALK) protein was performed on all cases of ALCL. Clinical features, response to therapy and survival were abstracted. Ninety-two cases of PTCL with adequate clinical information were retrieved. There were 40 cases of ALCL (30 classical, 7 small cell variant, 3 primary cutaneous), 28 PTCL, unspecified, 13 angioimmunoblastic T-cell lymphoma and 11 with other entities. The patients had a median age of 48 years with a range of 6-84 and had an estimated overall survival (OS) of 49% and progression-free survival (PFS) of 22% at 5 years. The International Prognostic Index (IPI) was a significant prognostic factor for both progression-free and OS. Histology was a significant predictor of PFS with anaplastic large cell having the best prognosis. ALK expression was not associated with an improved progression-free or overall-survival in patients with systemic T-cell ALCL. In conclusion, the REAL classification describes distinct PTCL entities. The IPI is the most important predictor of progression-free and OS in patients with PTCL. ALK expression may not provide prognostic information for systemic ALCL.
Leukemia and Lymphoma 03/2003; 44(2):241-9. · 2.58 Impact Factor
