Hillard M Lazarus

Case Western Reserve University, Cleveland, Ohio, United States

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Publications (566)3498.78 Total impact

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    ABSTRACT: Cystic fibrosis (CF) is a genetic disease in which the battle between pulmonary infection and inflammation becomes the major cause of morbidity and mortality. We have previously shown that human MSCs (hMSCs) decrease inflammation and infection in the in vivo murine model of CF. The studies in this paper focus on the specificity of the hMSC antimicrobial effectiveness using Pseudomonas aeruginosa (gram negative bacteria) and Staphylococcus aureus (gram positive bacteria). Our studies show that hMSCs secrete bioactive molecules which are antimicrobial in vitro against Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumonia , impacting the rate of bacterial growth and transition into colony forming units regardless of the pathogen. Further, we show that the hMSCs have the capacity to enhance antibiotic sensitivity, improving the capacity to kill bacteria. We present data which suggests that the antimicrobial effectiveness is associated with the capacity to slow bacterial growth and the ability of the hMSCs to secrete the antimicrobial peptide LL-37. Lastly, our studies demonstrate that the tissue origin of the hMSCs (bone marrow or adipose tissue derived), the presence of functional cystic fibrosis transmembrane conductance regulator (CFTR: human, Cftr : mouse) activity, and response to effector cytokines can impact both hMSC phenotype and antimicrobial potency and efficacy. These studies demonstrate, the unique capacity of the hMSCs to manage different pathogens and the significance of their phenotype in both the antimicrobial and antibiotic enhancing activities.
    Preview · Article · Jan 2016 · Stem cell International
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    ABSTRACT: Initial report of the ECOG-ACRIN Cancer Research Group trial E1900 (NCT00049517) showed that induction therapy with high dose (HD) daunorubicin (90 mg/m(2)) improved overall survival (OS) in adults less than 60 years with acute myeloid leukemia (AML); however, at initial analysis, benefit was restricted to younger patients (<50 years) and patients without unfavorable cytogenetics or a FLT3-ITD mutation. Here, we update the results of E1900 after longer follow-up (median 80.1 months among survivors) focusing on the benefit of HD daunorubicin on common genetic subgroups. Compared to standard dose (SD) daunorubicin (45 mg/m(2)), HD daunorubicin is associated with a hazard ratio (HR) for death of 0.74 (P = .001). Younger patients (<50 years) benefited from HD daunorubicin (HR, 0.66; P = .002), as did patients with favorable and intermediate cytogenetics (HR, 0.51; P = .03 and HR, 0.68; P = .01 respectively). Patients with unfavorable cytogenetics were shown to benefit from HD daunorubicin on multivariable analysis (adjusted HR, 0.66; P = .04). Patients with FLT3-ITD (24%), DNMT3A (24%), and NPM1 (26%) mutant AML all benefited from HD daunorubicin (HR, 0.61, P = .009; HR, 0.62, P = .02; and HR, 0.50, P = .002 respectively). High dose benefit was seen in the subgroup of older patients (50-60 years) with FLT3-ITD or NPM1 mutation. Additionally, the presence of an NPM1 mutation confers a favorable prognosis only for patients receiving anthracycline dose intensification during induction.
    No preview · Article · Jan 2016 · Blood
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    ABSTRACT: For adults with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1), allogeneic hematopoietic cell transplantation (HCT) is an established curative strategy. However, pediatric-inspired chemotherapy may also offer durable leukemia free survival in the absence of HCT. We compared 422 HCT recipients aged 18-50 years with Ph-ALL in CR1 reported to the CIBMTR with an age-matched concurrent cohort of 108 Ph- ALL CR1 patients who received a Dana-Farber Consortium pediatric-inspired non-HCT regimen. At four years follow-up, incidence of relapse after HCT was 24% [95% C.I. 19-28] vs. 23% [95% C.I. 15-32] for the non-HCT ("chemo") cohort (p=0.97). Treatment-related mortality (TRM) was higher in the HCT cohort (HCT 37% [95% C.I. 31-42] vs. chemo 6% [95% C.I. 3 - 12], p<0.0001). DFS in the HCT cohort was 40% [95% C.I. 35-45] vs. 71% [95% C.I. 60-79] for chemo, p<0.0001. Similarly, OS favored chemo (HCT 45% [95% C.I. 40-50]) vs. chemo 73% [95% C.I. 63-81], p<0.0001). In multivariable analysis, the sole factor predictive of shorter OS was the administration of HCT (HR 3.12 [1.99 - 4.90], p<0.0001). For younger adults with Ph- ALL, pediatric-inspired chemotherapy had lower TRM, no increase in relapse, and superior overall survival compared to HCT. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · American Journal of Hematology
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    ABSTRACT: We evaluated 917 adult lymphoma patients who received haploidentical (n=185) or HLA-matched unrelated donor (URD) transplantation either with (n=241) or without anti-thymocyte globulin (ATG; n=491), following reduced-intensity conditioning regimens. Haploidentical recipients received post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3-years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate-analysis was 8%, 12% and 17% in the haploidentical, URD without ATG and URD with ATG groups, respectively, p=0.44. Corresponding 1-year rates of chronic GVHD on univariate-analysis were 13%, 51% and 33% respectively, p<0.001. On multivariate analysis grade III-IV acute GVHD was higher in URD without ATG (p=0.001), as well as URD with ATG (p=0.01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants risk of chronic GVHD was higher in URD without ATG and URD with ATG (p<0.0001). Cumulative incidence of relapse/progression at 3-years was 36%, 28% and 36% in the haploidentical, URD without ATG and URD with ATG groups, respectively, p=0.07. Corresponding 3-year overall survival was 60%, 62% and 50% in the three groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (p=0.21) or URD with ATG (p=0.16), relative to haploidentical transplants. Multivariate analysis showed no difference between the three groups in terms of non-relapse mortality, relapse/progression and progression-free survival. These data suggest that, reduced-intensity conditioning haploidentical transplantation with post-transplant cyclophosphamide does not compromise early survival outcomes compared to matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD.
    No preview · Article · Dec 2015 · Blood
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    ABSTRACT: African-American (AA) breast cancer (BCa) survivors have higher mortality rates, more comorbidities and are less likely to meet national physical activity guidelines after diagnosis compared to Caucasian BCa survivors. We previously reported that a 20-week resistance exercise intervention coupled with a support group and home walking program, conducted using facilities and personnel at a community cancer support center, in Stage I-III AA BCa survivors improved strength, fitness and circulating C-peptide levels. Here, we report our findings on changes in quality of life (QoL) and other behavioral measures associated with this 20-week intervention and, discuss findings from a qualitative analysis of semi-structured patient interviews. We found a clinically relevant improvement in QoL using the Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B) (Baseline, B: 101.1 ± 21.5; End-of-Intervention, EOI: 108.5 ± 21.6; p = 0.05) and, a significant decrease in depression using the Beck Depression Inventory-II (B: 11.9 ± 8.1; EOI: 9.0 ± 5.5; p = 0.03). Our analysis of the patient interviews support improvements in these behavioral measures in that participants stated that they "feel better", were "more motivated" and "uplifted" after the program. The patient interviews also provided insights to the primary motivators (e.g., social support, improvements in strength and function, weight loss) and barriers (e.g., family and health issues) in adhering to the program and provided suggestions for improving the program (e.g., incorporating nutritional and treatment related side-effect discussions). Our results suggest that community-based lifestyle interventions may improve QoL and depression in AA BCa survivors and lend insights for improving future programs.
    Full-text · Article · Dec 2015
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    ABSTRACT: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients requiring initial therapy are often older and frailer and unsuitable candidates for standard chemoimmunotherapy regimens. Shorter duration combination monoclonal antibody (mAb) therapy using alemtuzumab and rituximab has been shown to be effective and tolerable treatment for CLL. Standard dose anti-CD20 mAb therapy causes loss of CD20 expression by surviving CLL cells, which can be minimized by decreasing the mAb dose. We report a randomized phase II clinical trial enrolling older (≥ 65 years) patients (median age 76 years, n=31) with treatment naïve progressive CLL. Patients received 8-12 weeks of standard subcutaneous alemtuzumab with either intravenous standard (375 mg/m(2) weekly)(n=16) or low dose (20 mg/m(2) 3x week)(n=15) rituximab. This study was closed before full accrual because the manufacturer withdrew alemtuzumab for treatment of CLL. The overall response rate was 90% with an 45% complete response rate, median progression free survival of 17.9 months and no significant differences in outcome between the low and standard dose rituximab arms. The major toxicities were cytopenia and infection with one treatment fatality caused by progressive multifocal leukoencephalopathy but no other opportunistic infections. Combination mAb therapy was effective and tolerable treatment for older and frailer patients with progressive CLL, achieving a high rate of complete remissions. These data support the role of mAb in therapy for less fit CLL patients and the further study of low dose higher frequency anti-CD20 mAb therapy as a potentially more effective use of anti-CD20 mAb in the treatment of CLL. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · American Journal of Hematology
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    ABSTRACT: Septic transfusion reactions (STR) resulting from transfusion of bacterially contaminated platelets are a major hazard of platelet transfusion despite recent interventions. Active and passive surveillance for bacterially contaminated platelets were performed over 7-years (2007-2013) by culture of platelet aliquots at time of transfusion and review of reported transfusion reactions. All platelet units had been cultured 24 h after collection and released as negative. Five sets of STR criteria were evaluated, including recent AABB criteria, and sensitivity and specificity of these criteria, as well as of detection by active and passive surveillance, were determined. Twenty of 51,440 platelet units transfused (0.004%; 389/million) were bacterially contaminated by active surveillance and resulted in 5 STR occurring 9-24 h post-transfusion; none of these STR had been reported by passive surveillance. STR occurred only in neutropenic patients transfused with high bacterial loads. A total of 284 transfusion reactions (0.55%) were reported by passive surveillance. None of these patients had received contaminated platelets. However, 6 to 93 (2.1-32.7%) of these 284 reactions met one or more STR criteria, and sensitivity of STR criteria varied from 5.1% to 45.5%. These results document the continued occurrence of bacterial contamination of platelets resulting in STR in neutropenic patients, failure of passive surveillance to detect STR and lack of specificity of STR criteria. These findings highlight the limitations of reported national STR data based on passive surveillance and the need to implement further measures to address this problem such as secondary testing or use of pathogen reduction technologies.
    No preview · Article · Nov 2015 · Blood
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    ABSTRACT: The cellular structures and mechanical properties of human mesenchymal stem cells (hMSCs) vary significantly during culture and with differentiation. Previously, studies to measure mechanics have provided divergent results using different quantitative parameters and mechanical models of deformation. Here, we examine hMSCs prepared for clinical use and subject them to mechanical testing conducive to the relevant deformability associated with clinical injection procedures. Micropipette aspiration of hMSCs shows deformation as a viscoelastic fluid, with little variation from cell to cell within a population. After two passages, hMSCs deform as viscoelastic solids. Further, for clinical applicability during stem cell migration in vivo, we investigated the ability of hMSCs to invade into micropillar arrays of increasing confinement from 12 to 8 μm spacing between adjacent micropillars. We find that hMSC samples with reduced deformability and cells that are more solid-like with passage are more easily able to enter the micropillar arrays. Increased cell fluidity is an advantage for injection procedures and optimization of cell selection based on mechanical properties may enhance efficacy of injected hMSC populations. However, the ability to invade and migrate within tight interstitial spaces appears to be increased with a more solidified cytoskeleton, likely from increased force generation and contractility. Thus, there may be a balance between optimal injection survival and in situ tissue invasion.
    No preview · Article · Nov 2015 · Annals of Biomedical Engineering
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    ABSTRACT: Anthracyclines are the cornerstone of therapy for a wide spectrum of malignancies and have improved patient survival. Concern for anthracycline-related cardiotoxicity often leads to dose reductions or use of second-line regimens, which may adversely impact survival. Development of cardiotoxicity depends on a combination of cumulative dose modulated by individual patient characteristics, which we have termed individual cardiotoxic threshold (ICT). Patients with cancer often have characteristics such as age, gender, genetic predisposition and preexisting cardiovascular disease that can potentiate cardiotoxicity. Specialty cardiovascular assessment, more sensitive monitoring technology, and timely interventions in selected patients can decrease cardiotoxicity and improve patient outcomes. Prophylaxis with cardioprotective agents and other strategies have shown promising results in randomized trials and may improve tolerance to anthracyclines. In this review we introduce the concept of ICT and critically analyze the evidence supporting existing strategies to modulate it and increase cardiovascular tolerability of anthracyclines.
    No preview · Article · Nov 2015 · Blood Reviews
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    ABSTRACT: Risk factors for non-Aspergillus mold infection (NAMI) and the impact on transplant outcome are poorly assessed in the current era of antifungal agents. Outcomes of 124 patients receiving allogeneic hematopoietic cell transplantation (HCT) diagnosed with either mucormycosis (n=72) or fusariosis (n=52) between days 0 and 365 after HCT are described and compared with a control cohort (n=11 856). Patients with NAMI had more advanced disease (mucormycois: 25%, fusariosis: 23% and controls: 18%; P=0.004) and were more likely to have a Karnofsky performance status (KPS) <90% at HCT (mucormycosis: 42%, fusariosis: 38% and controls: 28%; P=0.048). The 1-year survival after HCT was 22% (15-29%) for cases and was significantly inferior compared with controls (65% (64-65%); P<0.001). Survival from infection was similarly dismal regardless of mucormycosis: 15% (8-25%) and fusariosis: 21% (11-33%). In multivariable analysis, NAMI was associated with a sixfold higher risk of death (P<0.0001) regardless of the site or timing of infection. Risk factors for mucormycosis include preceding acute GvHD, prior Aspergillus infection and older age. For fusariosis, increased risks including receipt of cord blood, prior CMV infection and transplant before May 2002. In conclusion, NAMI occurs infrequently, is associated with high mortality and appears with similar frequency in the current antifungal era.Bone Marrow Transplantation advance online publication, 2 November 2015; doi:10.1038/bmt.2015.263.
    No preview · Article · Nov 2015 · Bone marrow transplantation
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    ABSTRACT: Recent investigations have found a higher incidence of adverse events associated with hematopoietic cell donation in related donors (RDs) who have morbidities that if present in an unrelated donor (UD) would preclude donation. In the UD setting, regulatory standards ensure independent assessment of donors, one of several crucial measures to safeguard donor health and safety. A survey conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) Donor Health and Safety Working Committee in 2007 reported a potential conflict of interest in >70% US centers, where physicians had simultaneous responsibility for RDs and their recipients. Consequently, several international organizations have endeavored to improve practice through regulations and consensus recommendations. We hypothesized that the changes in the 2012 FACT-JACIE Standards, resulting from the CIBMTR study, will have significantly impacted practice. Accordingly, a follow-up survey of US transplant centers was conducted to assess practice changes since 2007, and investigate additional areas where RD care was predicted to differ from UD care. 73 centers (53%), performing 79% of US RD transplants responded. Significant improvements were observed since the earlier survey; 62% centers now ensure separation of RD and recipient care (P<0.0001). However, this study identifies several areas where RD management does not meet international donor care standards. Particular concerns include counseling and assessment of donors before HLA typing, with 61% centers first disclosing donor HLA results to an individual other than the donor, the use of unlicensed mobilization agents, and the absence of long-term donor follow-up. Recommendations for improvement are described.
    No preview · Article · Nov 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.Bone Marrow Transplantation advance online publication, 5 October 2015; doi:10.1038/bmt.2015.223.
    Full-text · Article · Oct 2015 · Bone marrow transplantation
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    ABSTRACT: Purpose: Autologous hematopoietic cell transplantation, or autotransplantation, is effective in light-chain amyloidosis (AL), but it is associated with a high risk of early mortality (EM). In a multicenter randomized comparison against oral chemotherapy, autotransplantation was associated with 24% EM. We analyzed trends in outcomes after autologous hematopoietic cell transplantation for AL in North America. Patients and methods: Between 1995 and 2012, 1,536 patients with AL who underwent autotransplantation at 134 centers were identified in the Center for International Blood and Marrow Transplant Research database. EM and overall survival (OS) were analyzed in three time cohorts: 1995 to 2000 (n = 140), 2001 to 2006 (n = 596), and 2007 to 2012 (n = 800). Hematologic and renal responses and factors associated with EM, relapse and/or progression, progression-free survival and OS were analyzed in more recent subgroups from 2001 to 2006 (n = 197) and from 2007 to 2012 (n = 157). Results: Mortality at 30 and 100 days progressively declined over successive time periods from 11% and 20%, respectively, in 1995 to 2000 to 5% and 11%, respectively, in 2001 to 2006, and to 3% and 5%, respectively, in 2007 to 2012. Correspondingly, 5-year OS improved from 55% in 1995 to 2000 to 61% in 2001 to 2006 and to 77% in 2007 to 2012. Hematologic response to transplantation improved in the latest cohort. Renal response rate was 32%. Centers performing more than four AL transplantations per year had superior survival outcomes. In the multivariable analysis, cardiac AL was associated with high EM and inferior progression-free survival and OS. Autotransplantation in 2007 to 2012 and use of higher dosages of melphalan were associated with a lowered relapse risk. A Karnofsky score less than 80 and creatinine levels 2 mg/m(2) or greater were associated with worsened OS. Conclusion: Post-transplantation survival in AL has improved, with a dramatic reduction in early post-transplantation mortality and excellent 5-year survival. The risk-benefit ratio for autotransplantation has changed, and randomized comparison with nontransplantation approaches is again warranted.
    Full-text · Article · Sep 2015 · Journal of Clinical Oncology
  • Michael R. Jacobs · Hillard M. Lazarus · Robert W. Maitta
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    ABSTRACT: To the Editor: In their Perspective article on pathogen-reduction technology (PRT) (May 14 issue),(1) Snyder et al. praise the value of this technology. However, they omit a discussion of concerns about the safety and efficacy of PRT, stating that "Numerous studies demonstrate little substantive negative effect from pathogen reduction on plasma proteins or platelets." A study in the Netherlands was terminated because of increased bleeding complications in the PRT group,(2) and a U.S. study documented five fatal cases of the acute respiratory distress syndrome in the PRT group (1.6%) versus none in the control group.(3) Furthermore, PRT fails to inactivate . . .
    No preview · Article · Aug 2015 · New England Journal of Medicine
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    ABSTRACT: In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.Bone Marrow Transplantation advance online publication, 24 August 2015; doi:10.1038/bmt.2015.190.
    No preview · Article · Aug 2015 · Bone marrow transplantation
  • N Epperla · T S Fenske · H M Lazarus · M Hamadani
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    ABSTRACT: Disease relapse after autologous hematopoietic transplant (auto-HCT) remains the number one cause of post-transplant therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at the prevention of post-auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. Although high dose therapy (HDT) provides durable responses in chemosensitive relapsed diffuse large B-cell lymphoma (DLBCL), a sizable subset experiences disease relapse. Unfortunately, the addition of rituximab as a post-auto-HCT maintenance strategy did not improve survival outcomes. The preliminary results with programmed death -1 (PD-1) Ab as post-auto maintenance in DLBCL is promising but requires randomized validation. In follicular lymphoma, the 5- and 10-year PFS rates are ~60% and 31%, respectively. Although the addition of rituximab improved PFS, there is no survival benefit, to date. Disease relapse after auto-HCT in mantle cell lymphoma (MCL) is not uncommon. Rituximab maintenance in this setting provides a PFS benefit. Given the poor prognosis of post-auto-HCT failures in MCL, maintenance can be considered on a case-by-case basis. In chemosensitive relapsed Hodgkin lymphoma, addition of brentuximab vedotin after auto-HCT improved 2-year PFS (65 vs 45%) and can be considered as an option for maintenance therapy post auto-HCT, in select higher risk patients. Ongoing trials evaluating the efficacy of post-auto-HCT maintenance with novel agents (for example, immunomodulators, proteasome inhibitors, PD-1 inhibitors, Bruton's tyrosine kinase inhibitors and so on) will likely change the practice landscape for lymphoma patients following HDT and auto-HCT.Bone Marrow Transplantation advance online publication, 17 August 2015; doi:10.1038/bmt.2015.184.
    No preview · Article · Aug 2015 · Bone marrow transplantation
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    ABSTRACT: Comparison of long-term outcomes in patients with refractory/relapsed grade 1-2 follicular lymphoma (FL) after allogeneic (allo-HCT) vs. autologous hematopoietic cell transplantation (auto-HCT) in the rituximab-era. Adult patients with relapsed/refractory grade 1-2 FL undergoing 1(st) reduced-intensity allo-HCT or 1(st) autograft during 2000-2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger; more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto- vs. allo-HCT groups for non-relapse mortality (NRM) were 5% vs. 26% (p<0.0001); relapse/progression: 54% vs. 20% (p<0.0001); progression-free survival (PFS): 41% vs. 58% (p<0.001) and overall survival (OS): 74% vs. 66% (p=0.05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months post-HCT (RR=4.4; p<0.0001), and worse PFS (RR=2.9; p<0.0001) beyond 11 months post HCT. In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.41; p<0.0001), but beyond 24 months with inferior OS (RR=2.2; p=0.006). A landmark analysis of patients alive and progression-free at 2-years post-HCT confirmed these observations, showing no difference in further NRM between both groups, but significantly higher risk of relapse/progression (RR=7.3; p<0.0001) and inferior PFS (RR=3.2; p<0.0001) and OS (RR=2.1; p=0.04) following auto-HCT. The 10-year cumulative incidence of second hematological malignancies following allo- and auto-HCT was 0% and 7%, respectively. Auto- and RIC-allo-HCT as 1(st) transplantation approach can provide durable disease control in grade 1-2 FL patients. Continued disease relapse-risk following auto-HCT translates into improved PFS and OS following allo-HCT, in long-term survivors. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.Bone Marrow Transplantation advance online publication, 3 August 2015; doi:10.1038/bmt.2015.177.
    No preview · Article · Aug 2015 · Bone marrow transplantation
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    Preview · Article · Aug 2015
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    ABSTRACT: The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, N=240) and in myelodysplastic syndrome (MK+MDS, N=221) on hematopoietic cell transplantation (HCT) outcomes compared to other cytogenetically defined groups (AML, N=3,360; MDS, N=1,373) as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1998 to 2011. MK+AML was associated with higher disease relapse (hazard ratio [HR] 1.98, p<0.01), similar transplant related mortality (TRM, HR 1.01, p=0.9) and worse survival (HR 1.67, p<0.01) compared to other cytogenetically defined AML. Among patients with MDS, MK+MDS was associated with higher disease relapse (HR 2.39, p<0.01), higher TRM (HR 1.80, p<0.01) and worse survival (HR 2.02, p<0.01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (HR 1.72, p<0.01) and MDS (HR1.79, p<0.01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation

Publication Stats

22k Citations
3,498.78 Total Impact Points

Institutions

  • 1982-2016
    • Case Western Reserve University
      • • Division of Hematology and Oncology
      • • School of Medicine
      • • Case Comprehensive Cancer Center
      • • Department of Medicine (University Hospitals Case Medical Center)
      • • Institute of Pathology
      Cleveland, Ohio, United States
  • 2013-2015
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 1981-2015
    • Case Western Reserve University School of Medicine
      • • Department of Medicine
      • • Department of Physiology and Biophysics
      Cleveland, Ohio, United States
  • 1980-2015
    • Cleveland State University
      Cleveland, Ohio, United States
  • 2011
    • Roswell Park Cancer Institute
      Buffalo, New York, United States
  • 2008
    • British Society of Blood and Marrow Transplantation
      Bristol, England, United Kingdom
  • 2003-2007
    • Northwestern University
      • Division of Hematology/Oncology
      Evanston, Illinois, United States
  • 2006
    • Cardiff University
      Cardiff, Wales, United Kingdom
  • 2001-2006
    • Technion - Israel Institute of Technology
      H̱efa, Haifa, Israel
    • University of Nebraska at Omaha
      • Department of Internal Medicine
      Omaha, Nebraska, United States
  • 2005
    • University of Chicago
      • Section of Hematology/Oncology
      Chicago, Illinois, United States
  • 2004
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1996-2004
    • Medical College of Wisconsin
      • Center for International Blood & Marrow Transplant Research
      Milwaukee, WI, United States
  • 2002
    • University of Toronto
      Toronto, Ontario, Canada
  • 1999
    • Hôpital Maisonneuve-Rosemont
      Montréal, Quebec, Canada
  • 1995
    • University of South Florida
      • Department of Internal Medicine
      Tampa, Florida, United States
  • 1994
    • Centers for Disease Control and Prevention
      Atlanta, Michigan, United States
    • Baylor Health Care System
      Dallas, Texas, United States
  • 1993
    • University Of Miami Hospital
      Miami, Florida, United States
  • 1989
    • Vancouver General Hospital
      Vancouver, British Columbia, Canada
  • 1983-1989
    • Washington University in St. Louis
      • Division of Hematology and oncology
      San Luis, Missouri, United States
  • 1985-1987
    • Vanderbilt University
      • • Department of Preventive Medicine
      • • Department of Medicine
      Нашвилл, Michigan, United States
  • 1986
    • University of British Columbia - Vancouver
      • Faculty of Medicine
      Vancouver, British Columbia, Canada